ALOX15

Gene Summary

Gene:ALOX15; arachidonate 15-lipoxygenase
Aliases: 12-LOX, 15LOX-1, 15-LOX-1
Location:17p13.3
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:arachidonate 15-lipoxygenase
HPRD
Source:NCBIAccessed: 18 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 18 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Hydroxyeicosatetraenoic Acids
  • Up-Regulation
  • Transcription
  • Anti-Inflammatory Agents, Non-Steroidal
  • Signal Transduction
  • Promoter Regions
  • Transcription Factors
  • Sequence Homology, Nucleic Acid
  • RNA Splicing
  • Chromosome 17
  • RTPCR
  • Western Blotting
  • Immunohistochemistry
  • Arachidonate 12-Lipoxygenase
  • Tumor Burden
  • Cancer Gene Expression Regulation
  • Cell Differentiation
  • Angiogenesis
  • Colorectal Cancer
  • Base Sequence
  • Enzymologic Gene Expression Regulation
  • Messenger RNA
  • Down-Regulation
  • Tumor Suppressor Gene
  • Colonic Neoplasms
  • VEGFA
  • Transcriptional Activation
  • Prostaglandins
  • Apoptosis
  • STAT6 Transcription Factor
  • Arachidonate 15-Lipoxygenase
  • Tumor Markers
  • Transfection
  • COX2 (PTGS2)
  • Reticulocytes
  • PPARG
  • Linoleic Acids
  • Northern Blotting
  • Prostate Cancer
  • p53 Protein
Tag cloud generated 18 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ALOX15 (cancer-related)

Chen Y, Peng C, Abraham SA, et al.
Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival.
J Clin Invest. 2014; 124(9):3847-62 [PubMed] Free Access to Full Article Related Publications
Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML.

Suraneni MV, Moore JR, Zhang D, et al.
Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer.
Cell Cycle. 2014; 13(11):1798-810 [PubMed] Free Access to Full Article Related Publications
15-Lipoxygenase-2 (15-LOX2) is a human-specific lipid-peroxidizing enzyme most prominently expressed in epithelial cells of normal human prostate but downregulated or completely lost in>70% of prostate cancer (PCa) cases. Transgenic expression of 15-LOX2 in the mouse prostate surprisingly causes hyperplasia. Here we first provide evidence that 15-LOX2-induced prostatic hyperplasia does not progress to PCa even in p53(+/-) or p53(-/-) background. More important, by generating 15-LOX2; Hi-Myc double transgenic (dTg) mice, we show that 15-LOX2 expression inhibits Myc-induced PCa development, such that in the 3-month- and 6-month-old dTg mice, there is a significant reduction in prostate intraneoplasia (PIN) and PCa prevalent in age-matched Hi-Myc prostates. The dTg prostates show increased cell senescence and expression of several senescence-associated molecules, including p27, phosphorylated Rb, and Rb1cc1. We further show that in HPCa, 15-LOX2 and c-Myc manifest reciprocal protein expression patterns. Moreover, RB1CC1 accumulates in senescing normal human prostate (NHP) cells, and in both NHP and RWPE-1 cells, the 15-LOX2 metabolic products 15(S)-HPETE and 15(S)-HETE induce RB1CC1. We finally show that unlike 15-LOX2, RB1CC1 is not lost but rather frequently overexpressed in PCa samples. RB1CC1 knockdown in PC3 cells enhances clonal growth in vitro and tumor growth in vivo. Together, our present studies provide evidence for tumor-suppressive functions for both 15-LOX2 and RB1CC1.

Zhong H, Wang R, Kelavkar U, et al.
Enzyme 15-lipoxygenase 1 promotes hypoxia-inducible factor 1α turnover and reduces vascular endothelial growth factor expression: implications for angiogenesis.
Cancer Med. 2014; 3(3):514-25 [PubMed] Free Access to Full Article Related Publications
Hypoxia-inducible factor 1α (HIF-1α) is the regulatory subunit of the heterodimeric HIF-1 that plays a critical role in transcriptional regulation of genes in angiogenesis and hypoxic adaptation, while fatty acid metabolism mediated by lipoxygenases has been implicated in a variety of pathogeneses, including cancers. In this study, we report that 15-lipoxygenase 1 (15-LO1), a key member of the lipoxygenase family, promotes HIF-1α ubiquitination and degradation. Altering the level of 15-LO1 yields inverse changes in HIF-1α and HIF-1 transcriptional activity, under both normoxia and hypoxia, and even in CoCl2 -treated cells where HIF-1α has been artificially elevated. The antagonistic effect of 15-LO1 is mediated by the Pro(564) /hydroxylation/26S proteasome system, while both the enzymatic activity and the intracellular membrane-binding function of 15-LO1 appear to contribute to HIF-1α suppression. Our findings provide a novel mechanism for HIF-1α regulation, in which oxygen-dependent HIF-1 activity is modulated by an oxygen-insensitive lipid metabolic enzyme.

Wu Y, Mao F, Zuo X, et al.
15-LOX-1 suppression of hypoxia-induced metastatic phenotype and HIF-1α expression in human colon cancer cells.
Cancer Med. 2014; 3(3):472-84 [PubMed] Free Access to Full Article Related Publications
The expression of 15-lipoxygenase-1 (15-LOX-1) is downregulated in colon cancer and other major cancers, and 15-LOX-1 reexpression in cancer cells suppresses colonic tumorigenesis. Various lines of evidence indicate that 15-LOX-1 expression suppresses premetastatic stages of colonic tumorigenesis; nevertheless, the role of 15-LOX-1 loss of expression in cancer epithelial cells in metastases continues to be debated. Hypoxia, a common feature of the cancer microenvironment, promotes prometastatic mechanisms such as the upregulation of hypoxia-inducible factor (HIF)-1α, a transcriptional master regulator that enhances cancer cell metastatic potential, angiogenesis, and tumor cell invasion and migration. We have, therefore, tested whether restoring 15-LOX-1 in colon cancer cells affects cancer cells' hypoxia response that promotes metastasis. We found that 15-LOX-1 reexpression in HCT116, HT29LMM, and LoVo colon cancer cells inhibited survival, vascular endothelial growth factor (VEGF) expression, angiogenesis, cancer cell migration and invasion, and HIF-1α protein expression and stability under hypoxia. These findings demonstrate that 15-LOX-1 expression loss in cancer cells promotes metastasis and that therapeutically targeting ubiquitous 15-LOX-1 loss in cancer cells has the potential to suppress metastasis.

Sain S, Naoghare PK, Devi SS, et al.
Beta caryophyllene and caryophyllene oxide, isolated from Aegle marmelos, as the potent anti-inflammatory agents against lymphoma and neuroblastoma cells.
Antiinflamm Antiallergy Agents Med Chem. 2014; 13(1):45-55 [PubMed] Related Publications
Aegle marmelos (Indian Bael) is a tree which belongs to the family of Rutaceae. It holds a prominent position in both Indian medicine and Indian culture. We have screened various fractions of Aegle marmelos extracts for their anticancer properties using in vitro cell models. Gas chromatography-Mass spectrometry (GC-MS) was employed to analyze the biomolecules present in the Aegle marmelos extract. Jurkat and human neuroblastoma (IMR-32) cells were treated with different concentrations of the fractionated Aegle marmelos extracts. Flow cytometric analysis revealed that optimal concentration (50 µg/ml) of beta caryophyllene and caryophyllene oxide fractions of Aegle marmelos extract can induce apoptosis in Jurkat cell line. cDNA expression profiling of pro-apoptotic and anti-apoptotic genes was carried out using real time PCR (RT-PCR). Down-regulation of anti-apoptotic genes (bcl-2, mdm2, cox2 and cmyb) and up-regulation of pro-apoptotic genes (bax, bak1, caspase-8, caspase-9 and ATM) in Jurkat and IMR-32 cells treated with the beta caryophyllene and caryophyllene oxide fractions of Aegle marmelos extract revealed the insights of the downstream apoptotic mechanism. Furthermore, in-silico approach was employed to understand the upstream target involved in the induction of apoptosis by the beta caryophyllene and caryophyllene oxide fractions of Aegle marmelos extract. Herein, we report that beta caryophyllene and caryophyllene oxide isolated from Aegle marmelos can act as potent anti-inflammatory agents and modulators of a newly established therapeutic target, 15-lipoxygenase (15-LOX). Beta caryophyllene and caryophyllene oxide can induce apoptosis in lymphoma and neuroblastoma cells via modulation of 15-LOX (up-stream target) followed by the down-regulation of anti-apoptotic and up-regulation of pro-apoptotic genes.

Hughes L, Ruth K, Rebbeck TR, Giri VN
Genetic variation in IL-16 miRNA target site and time to prostate cancer diagnosis in African-American men.
Prostate Cancer Prostatic Dis. 2013; 16(4):308-14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Men with a family history of prostate cancer and African-American men are at high risk for prostate cancer and in need of personalized risk estimates to inform screening decisions. This study evaluated genetic variants in genes encoding microRNA (miRNA) binding sites for informing of time to prostate cancer diagnosis among ethnically diverse, high-risk men undergoing prostate cancer screening.
METHODS: The Prostate Cancer Risk Assessment Program (PRAP) is a longitudinal screening program for high-risk men. The eligibility includes men aged between 35 and 69 years with a family history of prostate cancer or African descent. Participants with 1 follow-up visit were included in the analyses (n=477). Genetic variants in genes encoding miRNA binding sites (ALOX15 (arachidonate 15-lipooxygenase), IL-16, IL-18 and RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)) previously implicated in prostate cancer development were evaluated. Genotyping methods included Taqman SNP Genotyping Assay or pyrosequencing. Cox models were used to assess time to prostate cancer diagnosis by risk genotype.
RESULTS: Among 256 African Americans with one follow-up visit, the TT genotype at rs1131445 in IL-16 was significantly associated with earlier time to prostate cancer diagnosis vs the CC/CT genotypes (P=0.013), with a suggestive association after correction for false discovery (P=0.065). Hazard ratio after controlling for age and PSA for TT vs CC/CT among African Americans was 3.0 (95% confidence interval: 1.26-7.12). No association with time to diagnosis was detected among Caucasians by IL-16 genotype. No association with time to prostate cancer diagnosis was found for the other miRNA target genotypes.
CONCLUSIONS: Genetic variation in IL-16 encoding miRNA target site may be informative of time to prostate cancer diagnosis among African-American men enrolled in prostate cancer risk assessment, which may inform individualized prostate cancer screening strategies in the future.

Li S, Zhao X, Wu Z, et al.
Polymorphisms in arachidonic acid metabolism-related genes and the risk and prognosis of colorectal cancer.
Fam Cancer. 2013; 12(4):755-65 [PubMed] Related Publications
Cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LOX) and phospholipaseA2 (PLA2) played important roles in the modulation of apoptosis, angiogenesis, carcinogenesis and invasion of colorectal cancer (CRC). The polymorphisms in COX-2, 12-LOX and PLA2 may affect their roles. Therefore, we investigated if COX-2 -1195G > A, 12-LOX 261Arg > Gln and PLA2 c.349 + 191A > G polymorphisms were associated with risk and prognosis of CRC as well as possible interactions with the environmental factors on the risk of CRC in Northeast of China. A case-control study with 451 cases and 631 controls were carried out, a cohort with 386 patients were followed up. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Compared with the 261Arg/Arg genotype, 12-LOX 261Arg/Gln genotype and 261Arg/Gln + Gln/Gln genotypes reduced the risk of rectal cancer by 33% (adjusted OR = 0.67, 95% CI 0.47-0.97, p = 0.03) and 32% (adjusted OR = 0.68, 95% CI 0.49-0.96, p = 0.03), respectively. The adjusted HR for the association between 12-LOX 261Gln/Gln genotype and overall survival in patients with CRC was 1.68 (95% CI 1.06-2.68, p = 0.03). There was also evidence of an interaction between the PLA2 c.349 + 191 A > G genotypes and the overnight food consumption (adjusted ORi = 1.92, 95% CI 1.14-3.25, P(interaction) = 0.01). These observations indicate that 12-LOX 261Arg > Gln polymorphism may affect risk of rectal cancer, and it may be a potential predictive marker for prognosis of CRC.

Dilly AK, Ekambaram P, Guo Y, et al.
Platelet-type 12-lipoxygenase induces MMP9 expression and cellular invasion via activation of PI3K/Akt/NF-κB.
Int J Cancer. 2013; 133(8):1784-91 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of death in males in the United States. Using human prostate cancer specimens, the authors have previously shown that elevated expression levels of 12-lipoxygenase (12-LOX) occurred more frequently in advanced stage, high-grade prostate cancer, suggesting that 12-LOX expression is associated with carcinoma progression and invasion. Previous reports from their group and others have shown that 12-LOX is a positive modulator of invasion and metastasis; however, the mechanism remains unclear. In this work, a new link between 12-LOX and the matrix metalloproteinase 9 (MMP9) in prostate cancer angiogenesis is reported. This study demonstrated that overexpression of 12-LOX in prostate cancer PC-3 cells resulted in elevated expression of MMP9 mRNA, protein and secretion. Exogenous addition of 12(S)-hydroxy eicosatetraenoic acid, the sole and stable end product of arachidonic acid metabolism by 12-LOX, is able to increase MMP9 expression in wild-type PC-3 cells. Furthermore, using pharmacological and genetic inhibition approaches, it was found that 12-LOX activates phosphoinositol 3 kinase (PI3K)/Akt, which results in nuclear factor-kappa B (NF-κB)-driven MMP9 expression, ensuing in enhanced chemoattraction of endothelial cells. Specific inhibitors of 12-LOX, PI3K or NF-κB inhibited MMP9 expression in 12-LOX-expressing PC-3 cells and resulted in the blockade of the migratory ability of endothelial cells. In summary, the authors have identified a new pathway by which overexpression of 12-LOX in prostate cancer cells leads to augmented production of MMP9 via activation of PI3K/Akt/NF-κB signaling. The role of 12-LOX-mediated MMP9 secretion in endothelial cell migration may account for the proangiogenic function of 12-LOX in prostate cancer.

Lövey J, Nie D, Tóvári J, et al.
Radiosensitivity of human prostate cancer cells can be modulated by inhibition of 12-lipoxygenase.
Cancer Lett. 2013; 335(2):495-501 [PubMed] Related Publications
Nearly 30% of prostate cancer (PCa) patients treated with potentially curative doses relapse at the sites of irradiation. How some tumor cells acquire radioresistance is poorly understood. The platelet-type 12-lipoxygenases (12-LOX)-mediated arachidonic acid metabolism is important in PCa progression. Here we show that 12-LOX confers radioresistance upon PCa cells. Treatment with 12-LOX inhibitors baicalein or BMD122 sensitizes PCa cells to radiation, without radiosensitizing normal cells. 12-LOX inhibitors and radiation, when combined, have super additive or synergistic inhibitory effects on the colony formation of both androgen-dependent LNCaP and androgen-independent PC-3 PCa cells. In vivo, the combination therapy significantly reduced tumor growth.

Kleinstein SE, Heath L, Makar KW, et al.
Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia.
Genes Chromosomes Cancer. 2013; 52(5):437-49 [PubMed] Free Access to Full Article Related Publications
Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation-associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with nonsteroidal anti-inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population-based case-control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had a decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wild type = 5, OR>5/≥5 = 0.42, 95% CI 0.20-0.92; P = 0.01). Four SNPs in FLAP (rs17239025), ALOX12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at P ≤ 0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in ALOXs may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia.

Zuo X, Shureiqi I
Eicosanoid profiling in colon cancer: emergence of a pattern.
Prostaglandins Other Lipid Mediat. 2013 Jul-Aug; 104-105:139-43 [PubMed] Free Access to Full Article Related Publications
Oxidative metabolism of polyunsaturated fatty acids has been linked to tumorigenesis in general and colonic tumorigenesis in particular. Earlier studies showed that cyclooxygenase-2 (COX-2) and 15-lipoxygenase-1 (15-LOX-1) have opposing impacts on colonic tumorigenesis: COX-2 promotes while 15-LOX-1 inhibits colonic tumorigenesis. Advances in liquid chromatography/mass spectrometry have allowed for measurement of various products of oxidative metabolism in a single colonic biopsy specimen. Studies of LOX products in preclinical models and in patients with familial adenomatous polyposis and sporadic colorectal tumorigenesis indicate that LOX pathways are shifted during colonic tumorigenesis and that the main shift is downregulation of 15-LOX-1. This shift occurs during the polyp formation stage and thus offers the opportunity to modulate tumorigenesis early by correcting 15-LOX-1 downregulation.

Yang P, Cartwright CA, Li J, et al.
Arachidonic acid metabolism in human prostate cancer.
Int J Oncol. 2012; 41(4):1495-503 [PubMed] Free Access to Full Article Related Publications
The arachidonic acid pathway is important in the development and progression of numerous malignant diseases, including prostate cancer. To more fully evaluate the role of individual cyclooxygenases (COXs), lipoxygenases (LOXs) and their metabolites in prostate cancer, we measured mRNA and protein levels of COXs and LOXs and their arachidonate metabolites in androgen-dependent (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cell lines, bone metastasis-derived MDA PCa 2a and MDA PCa 2b cell lines and their corresponding xenograft models, as well as core biopsy specimens of primary prostate cancer and nonneoplastic prostate tissue taken ex vivo after prostatectomy. Relatively high levels of COX-2 mRNA and its product PGE2 were observed only in PC-3 cells and their xenografts. By contrast, levels of the exogenous 12-LOX product 12-HETE were consistently higher in MDA PCa 2b and PC-3 cells and their corresponding xenograft tissues than were those in LNCaP cells. More strikingly, the mean endogenous level of 12-HETE was significantly higher in the primary prostate cancers than in the nonneoplastic prostate tissue (0.094 vs. 0.010 ng/mg protein, respectively; p=0.019). Our results suggest that LOX metabolites such as 12-HETE are critical in prostate cancer progression and that the LOX pathway may be a target for treating and preventing prostate cancer.

Prasad VV, Padma K
Non-synonymous polymorphism (Gln261Arg) of 12-lipoxygenase in colorectal and thyroid cancers.
Fam Cancer. 2012; 11(4):615-21 [PubMed] Related Publications
12-lipoxygenase (12-LOX) pathway which produces 12-HETE and hepoxiline HXA3 and HXB3, and induces production of reactive oxygen species and inflammation is increasingly being implicated in variety of cancers, including those of colorectal and thyroid cancers. Hence, we examined whether the functional polymorphism of 12-LOX (mRNA A835G; Protein Gln261Arg) has any association with human colorectal and thyroid cancers. In this communication, we report that the mutation is linked to colorectal cancer and thyroid cancers. Further, we also observed that the heterozygous mutant (AG) is more prevalent in females than in males. Frequencies of AA, AG and GG, respectively were 62.5, 36.2 and 1.3 % in controls, 36.5, 61.5 and 2.0 % in colorectal cancer cases and 35.6, 62.4 and 2.0 % in thyroid cancer cases. The results obtained suggested a significant association of the heterogenous variant (AG) with the cancers. Relative risk of the cancers with the presence of the AG variant was found to be 2.9 and 4.0 for colorectal and thyroid cancers, respectively. However, the association of the variant (AG) was significant only in male colorectal cancer patients but not in female patients. On the other hand, prevalence of the AG variant is significantly higher in control females than in male control subjects. To the best of our knowledge, this is the first study that links the 12-LOX gene polymorphism with thyroid cancer and reveals a gender bias in the prevalence of the polymorphic variants in controls and colorectal cancer patients.

Wang G, Liu L, Sharma S, et al.
Bmi-1 confers adaptive radioresistance to KYSE-150R esophageal carcinoma cells.
Biochem Biophys Res Commun. 2012; 425(2):309-14 [PubMed] Related Publications
Radiotherapy (RT) is a major modality of cancer treatment. However, tumors often acquire radioresistance, which causes RT to fail. The exact mechanisms by which tumor cells subjected to fractionated irradiation (FIR) develop an adaptive radioresistance are largely unknown. Using the radioresistant KYSE-150R esophageal squamous cell carcinoma (ESCC) model, which was derived from KYSE-150 parental cells using FIR, the role of Bmi-1 in mediating the radioadaptive response of ESCC cells to RT was investigated. The results showed that the level of Bmi-1 expression was significantly higher in KYSE-150R cells than in the KYSE-150 parental cells. Bmi-1 depletion sensitized the KYSE-150R cells to RT mainly through the induction of apoptosis, partly through the induction of senescence. A clonogenic cell survival assay showed that Bmi-1 depletion significantly decreased the radiation survival fraction in KYSE-150R cells. Furthermore, Bmi-1 depletion increased the generation of reactive oxygen species (ROS) and the expression of oxidase genes (Lpo, Noxo1 and Alox15) in KYSE-150R cells exposed to irradiation. DNA repair capacities assessed by γ-H2AX foci formation were also impaired in the Bmi-1 down-regulated KYSE-150R cells. These results suggest that Bmi-1 plays an important role in tumor radioadaptive resistance under FIR and may be a potent molecular target for enhancing the efficacy of fractionated RT.

Xu XM, Yuan GJ, Deng JJ, et al.
Inhibition of 12-lipoxygenase reduces proliferation and induces apoptosis of hepatocellular carcinoma cells in vitro and in vivo.
Hepatobiliary Pancreat Dis Int. 2012; 11(2):193-202 [PubMed] Related Publications
BACKGROUND: 12-lipoxygenase (12-LOX) has been reported to be an important gene in cancer cell proliferation and survival, and tumor metastasis. However, its role in hepatocellular carcinoma (HCC) cells remains unknown.
METHODS: Expression of 12-LOX was assessed in a diethyl-nitrosamine-induced rat HCC model, and in SMMC-7721, HepG2 and L-02 cells using immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). GST-π and Ki-67 were determined in vivo by immunohistochemical staining. Apoptosis was evaluated by TUNEL assay. Cell viability and apoptosis were determined by MTT assay and flow cytometry, respectively. Apoptosis-related proteins in SMMC-7721 and HepG2 cells were detected by Western blotting.
RESULTS: Immunohistochemical staining and RT-PCR showed that 12-LOX was over-expressed in rat HCC and two HCC cell lines, while the expression was inhibited by baicalein, a specific inhibitor of 12-LOX. Baicalein inhibited cell proliferation and induced apoptosis in rat HCC and both cell lines in a dose- and time-dependent manner. Our in vivo study demonstrated that baicalein also reduced neoplastic nodules. Mechanistically, baicalein reduced Bcl-2 protein expression coupled with a slight increase of the expression of Bax and activation of caspase-3. Furthermore, baicalein inhibited the activation of ERK-1/2 (phosphorylated). Interestingly, the effects of baicalein were reversed by 12(S)-HETE, a metabolite of 12-LOX.
CONCLUSIONS: Inhibition of 12-LOX leads to reduced numbers of HCC cells, partially caused by increased apoptosis. 12-LOX may be a potential molecular target for HCC prevention and treatment.

Viita H, Pacholska A, Ahmad F, et al.
15-Lipoxygenase-1 induces lipid peroxidation and apoptosis, and improves survival in rat malignant glioma.
In Vivo. 2012 Jan-Feb; 26(1):1-8 [PubMed] Related Publications
BACKGROUND: Previous studies suggest either an anti- or pro-apoptotic role for 15-lipoxygenase-1 in carcinogenesis.
MATERIALS AND METHODS: We used adenovirus gene transfer of human 15-lipoxygenase-1 to characterize its effects in vitro and in vivo.
RESULTS: 15-Lipoxygenase-1 expression in mouse macrophages resulted in a significant, 25-fold, induction in the production of the specific 15-lipoxygenase-1 product 13-hydroxyoctadecadienoic acid. Tail vein gene transfers in mice led to highest expression of the transduced 15-lipoxygenase-1 in liver and spleen. In the liver, 15-lipoxygenase-1 significantly increased lipid peroxidation by 3.5-fold and 2-fold, three and seven days after transduction, respectively. A significant 32-fold induction in caspase-3 activity was detected in 15-lipoxygenase-1 expressing livers seven days after transduction. In a syngeneic rat model of malignant glioma, 15-lipoxygenase-1 extended survival significantly (p=0.001).
CONCLUSION: Our results support the pro-apoptotic role of 15-lipoxygenase-1 and suggest that 15-lipoxygenase-1 could be a potential new target gene for the therapy of malignant glioma.

Liu C, Schain F, Han H, et al.
Epigenetic and transcriptional control of the 15-lipoxygenase-1 gene in a Hodgkin lymphoma cell line.
Exp Cell Res. 2012; 318(3):169-76 [PubMed] Related Publications
Lipoxygenases oxidatively metabolize polyunsaturated fatty acids to a rich spectrum of biologically active metabolites. The present study aimed at delineating the transcriptional and epigenetic mechanisms leading to 15-lipoxygenase-1 (15-LOX-1) expression in the Hodgkin lymphoma (HL) cell line L1236. Examination of the 15-LOX-1 5' promoter region demonstrated three putative binding sites for signal transducer and activator of transcription (STAT6) within the proximal 1200 base pairs relative to the start codon. Analysis by serial promoter deletions and STAT6 binding site mutations indicated that all three STAT6 binding sites are required for full activation of the 15-LOX-1 promoter. Chromatin immunoprecipitation assay demonstrated that these regions were occupied by STAT6 in L1236 (15-LOX-1 positive) but not in L428 (15-LOX-1 negative) cultured HL cells. Furthermore, DNA hypomethylation and histone hyperacetylation were detectable within the core promoter region of 15-LOX-1 only in L1236 cells but not L428 cells. Taken together, our data indicate that STAT6 activation and chromatin remodeling by DNA demethylation and histone acetylation are crucial for transcriptional activation of 15-LOX-1 in cultured HL cells. These prerequisites are fulfilled in the L1236 cell line, but not in the L428 cell line.

Pello OM, De Pizzol M, Mirolo M, et al.
Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology.
Blood. 2012; 119(2):411-21 [PubMed] Related Publications
In response to microenvironmental signals, macrophages undergo different activation, including the "classic" proinflammatory phenotype (also called M1), the "alternative" activation induced by the IL-4/IL-13 trigger, and the related but distinct heterogeneous M2 polarization associated with the anti-inflammatory profile. The latter is induced by several stimuli, including IL-10 and TGF-β. Macrophage-polarized activation has profound effects on immune and inflammatory responses and in tumor biology, but information on the underlying molecular pathways is scarce. In the present study, we report that alternative polarization of macrophages requires the transcription factor c-MYC. In macrophages, IL-4 and different stimuli sustaining M2-like polarization induce c-MYC expression and its translocation to the nucleus. c-MYC controls the induction of a subset (45%) of genes associated with alternative activation. ChIP assays indicate that c-MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1α, and TGF-β. We conclude that c-MYC is a key player in alternative macrophage activation, and is therefore a potential therapeutic target in pathologies related to these cells, including tumors.

Il Lee S, Zuo X, Shureiqi I
15-Lipoxygenase-1 as a tumor suppressor gene in colon cancer: is the verdict in?
Cancer Metastasis Rev. 2011; 30(3-4):481-91 [PubMed] Free Access to Full Article Related Publications
15-Lipoxygenase-1 (15-LOX-1) is an inducible and highly regulated enzyme in normal human cells that plays a key role in the production of lipid signaling mediators, such as 13-hydroxyoctadecadienoic acid (13-HODE) from linoleic acid. 15-LOX-1 significantly contributes to the resolution of inflammation and to the terminal differentiation of normal cells. 15-LOX-1 is downregulated in human colorectal polyps and cancers. Emerging data support a tumor suppressor role for 15-LOX-1, especially in colon cancer. These data indicate that 15-LOX-1 promotes various anti-tumorigenic events, including cell differentiation and apoptosis, and inhibits chronic inflammation, angiogenesis, and metastasis. The transcriptional repression of 15-LOX-1 in colon cancer cells is complex and involves multiple mechanisms (e.g., histone methylation, transcriptional repressor binding). Re-expression of 15-LOX-1 in colon cancer cells can function as an important therapeutic mechanism and could be further exploited to develop novel treatment approaches for this common cancer.

Wang X, Baek SJ, Eling T
COX inhibitors directly alter gene expression: role in cancer prevention?
Cancer Metastasis Rev. 2011; 30(3-4):641-57 [PubMed] Related Publications
Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development. NSAIDs also alter gene expression independent of COX inhibition and these changes in gene expression also appear to contribute to the anti-tumorigenic activity of these drugs. Many NSAIDs, as illustrated by sulindac sulfide, alter gene expressions by altering the expression or phosphorylation status of the transcription factors specificity protein 1 and early growth response-1 with the balance between these two events resulting in increases or decreases in specific target genes. In this review, we have summarized and discussed the various genes altered by this mechanism after NSAID treatment and how these changes in expression relate to the anti-tumorigenic activity. A major focus of the review is on NSAID-activated gene (NAG-1) or growth differentiation factor 15. This unique member of the TGF-β superfamily is highly induced by NSAIDs and numerous drugs and chemicals with anti-tumorigenic activities. Investigations with a transgenic mouse expressing the human NAG-1 suggest it acts to suppress tumor development in several mouse models of cancer. The biochemistry and biology of NAG-1 were discussed as potential contributor to cancer prevention by COX inhibitors.

Moussalli MJ, Wu Y, Zuo X, et al.
Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion.
Cancer Prev Res (Phila). 2011; 4(12):1961-72 [PubMed] Free Access to Full Article Related Publications
Loss of terminal cell differentiation promotes tumorigenesis. 15-Lipoxygenase-1 (15-LOX-1) contributes to terminal cell differentiation in normal cells. The mechanistic significance of 15-LOX-1 expression loss in human cancers to terminal cell differentiation suppression is unknown. In a screen of 128 cancer cell lines representing more than 20 types of human cancer, we found that 15-LOX-1 mRNA expression levels were markedly lower than levels in terminally differentiated cells. Relative expression levels of 15-LOX-1 (relative to the level in terminally differentiated primary normal human-derived bronchial epithelial cells) were lower in 79% of the screened cancer cell lines than relative expression levels of p16 (INK4A), which promotes terminal cell differentiation and is considered one of the most commonly lost tumor suppressor genes in cancer cells. 15-LOX-1 was expressed during terminal differentiation in three-dimensional air-liquid interface cultures, and 15-LOX-1 expression and terminal differentiation occurred in immortalized nontransformed bronchial epithelial but not in lung cancer cell lines. 15-LOX-1 expression levels were lower in human tumors than in paired normal lung epithelia. Short hairpin RNA-mediated downregulation of 15-LOX-1 in Caco-2 cells blocked enterocyte-like differentiation, disrupted tight junction formation, and blocked E-cadherin and ZO-1 localization to the cell wall membrane. 15-LOX-1 episomal expression in Caco-2 and HT-29 colon cancer cells induced differentiation. Our findings indicate that 15-LOX-1 downregulation in cancer cells is an important mechanism for terminal cell differentiation dysregulation and support the potential therapeutic utility of 15-LOX-1 reexpression to inhibit tumorigenesis.

Hsi LC, Kundu S, Palomo J, et al.
Silencing IL-13Rα2 promotes glioblastoma cell death via endogenous signaling.
Mol Cancer Ther. 2011; 10(7):1149-60 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is one of the most lethal forms of cancer, with a survival rate of only 13% to 27% within 2 years of diagnosis despite optimal medical treatment. We hypothesize that the presence of a unique IL-13Rα2 decoy receptor prevents GBM apoptosis. This receptor has a high affinity for interleukin-13 (IL-13), binds the cytokine, and competitively inhibits the intracellular signaling cascade initiated by IL-13. In cells lacking the IL-13Rα2 decoy receptor, IL-13 initiates the production of 15-lipoxygenase-1 (15-LOX-1), which has been implicated in cellular apoptosis. Our group and others have shown that induction of 15-LOX-1 correlates with tumor cell death in colorectal, pancreatic, and prostate cancer. How 15-LOX-1 induces apoptosis remains unclear. Preliminary evidence in GBM cells implicates an apoptotic process mediated by PPARγ. 15-LOX-1 metabolites can modulate PPARγ and activation of PPARγ can suppress tumor growth. We hypothesize that in GBM, IL-13 can induce 15-LOX-1, which regulates cell apoptosis via signaling through PPARγ and that expression of IL-13Rα2 prevents apoptosis and contributes to tumor growth. Our in vitro and in vivo data support this. Knocking down IL-13Rα2 with short interfering RNA dramatically induces 15-LOX-1 expression, promotes apoptosis, and reduces GBM tumor growth in vivo. These findings identify a mechanism for eliminating the blockade of endogenous IL-13 signaling and for promotion of apoptosis, and characterize a role for 15-LOX-1 in GBM apoptosis. Identifying a mechanistic pathway that can be targeted for pharmacologic intervention will have applied implications to developing novel and effective treatments of GBM.

Guo AM, Liu X, Al-Wahab Z, et al.
Role of 12-lipoxygenase in regulation of ovarian cancer cell proliferation and survival.
Cancer Chemother Pharmacol. 2011; 68(5):1273-83 [PubMed] Related Publications
PURPOSE: Eicosanoid-related enzymes have been implicated in the pathogenesis of various cancers. Little is known about the relevance of lipoxygenase pathway to ovarian cancer growth. In this study, we examined the role of 12-lipoxygenase (12-LOX), the main human 12-HETE generating enzyme, in the regulation of proliferation and survival in epithelial ovarian cancer.
METHODS: Immunohistological analysis of 12-LOX expression in high-grade serous ovarian carcinoma and normal ovarian epithelium tissues was performed. The presence of 12-LOX-12-HETE system was confirmed in two epithelial ovarian cancer (EOC) cell lines, OVCAR-3 and SK-OV-3, using RT-PCR, Western blot and LC/MS analysis. The effects of N-benzyl-N-hydroxy-5-phenyl-pentanamide (BMD-122), a specific 12-LOX inhibitor, on cell growth, survival, apoptosis, and cell signaling were determined.
RESULTS: We found that a significantly higher level of 12-LOX expression in high-grade serous ovarian carcinoma compared to normal ovarian epithelium. OVCAR-3 and SK-OV-3 were found to express high level of 12-LOX mRNA and protein. Both EOC increased their 12-HETE production when incubated with arachidonic acid. BMD-122 inhibited the EOC growth in a dose-dependent fashion. Purified 12-HETE significantly reversed such inhibitory effects of BMD-122. In addition, BMD-122 blocked the MAPK signaling pathway by inhibiting the phosphorylation of ERK and induced a ~20-30% increase in the EOC apoptosis. Down-regulation of the 12-LOX expression using 12-LOX siRNA also resulted in markedly reduction in cell growth.
CONCLUSIONS: These data suggest that 12-LOX is involved in the regulation of ovarian cancer cell growth and survival and is a potential new therapeutic target.

Mao JT, Nie WX, Tsu IH, et al.
White tea extract induces apoptosis in non-small cell lung cancer cells: the role of peroxisome proliferator-activated receptor-{gamma} and 15-lipoxygenases.
Cancer Prev Res (Phila). 2010; 3(9):1132-40 [PubMed] Free Access to Full Article Related Publications
Emerging preclinical data suggests that tea possess anticarcinogenic and antimutagenic properties. We therefore hypothesize that white tea extract (WTE) is capable of favorably modulating apoptosis, a mechanism associated with lung tumorigenesis. We examined the effects of physiologically relevant doses of WTE on the induction of apoptosis in non-small cell lung cancer cell lines A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cells. We further characterized the molecular mechanisms responsible for WTE-induced apoptosis, including the induction of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the 15-lipoxygenase (15-LOX) signaling pathways. We found that WTE was effective in inducing apoptosis in both A549 and H520 cells, and inhibition of PPAR-gamma with GW9662 partially reversed WTE-induced apoptosis. We further show that WTE increased PPAR-gamma activation and mRNA expression, concomitantly increased 15(S)-hydroxy-eicosatetraenoic acid release, and upregulated 15-LOX-1 and 15-LOX-2 mRNA expression by A549 cells. Inhibition of 15-LOX with nordihydroguaiaretic acid (NGDA), as well as caffeic acid, abrogated WTE-induced PPAR-gamma activation and upregulation of PPAR-gamma mRNA expression in A549 cells. WTE also induced cyclin-dependent kinase inhibitor 1A mRNA expression and activated caspase-3. Inhibition of caspase-3 abrogated WTE-induced apoptosis. Our findings indicate that WTE is capable of inducing apoptosis in non-small cell lung cancer cell lines. The induction of apoptosis seems to be mediated, in part, through the upregulation of the PPAR-gamma and 15-LOX signaling pathways, with enhanced activation of caspase-3. Our findings support the future investigation of WTE as an antineoplastic and chemopreventive agent for lung cancer.

Liu SH, Shen CC, Yi YC, et al.
Honokiol inhibits gastric tumourigenesis by activation of 15-lipoxygenase-1 and consequent inhibition of peroxisome proliferator-activated receptor-gamma and COX-2-dependent signals.
Br J Pharmacol. 2010; 160(8):1963-72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), COX-2 and 15-lipoxygenase (LOX)-1 have been shown to be involved in tumour growth. However, the roles of PPAR-gamma, COX-2 or 15-LOX-1 in gastric tumourigenesis remain unclear. Here, we investigate the role of 15-LOX-1 induction by honokiol, a small-molecular weight natural product, in PPAR-gamma and COX-2 signalling during gastric tumourigenesis.
EXPERIMENTAL APPROACH: Human gastric cancer cell lines (AGS, MKN45, N87 and SCM-1) were cultured with or without honokiol. Gene and protein expressions were analysed by RT-PCR and Western blotting respectively. Small interfering RNAs (siRNAs) for COX-2, PPAR-gamma and 15-LOX-1 were used to interfere with the expressions of these genes. A xenograft gastric tumour model in mouse was used for in vivo study.
KEY RESULTS: PPAR-gamma and COX-2 proteins were highly expressed in gastric cancer cells. Inhibitors, or siRNA for COX-2 or PPAR-gamma, significantly decreased cell viability. Honokiol markedly inhibited PPAR-gamma and COX-2 expressions in gastric cancer cells and tumours of xenograft mice, and induced apoptosis and cell death. Honokiol markedly activated cellular 15-LOX-1 expression and 13-S-hydroxyoctadecadienoic acid (a primary product of 15-LOX-1 metabolism of linoleic acid) production. 15-LOX-1 siRNA could reverse the honokiol-induced down-regulation of PPAR-gamma and COX-2, and cell apoptosis. 15-LOX-1 was markedly induced in tumours of xenograft mice treated with honokiol.
CONCLUSIONS AND IMPLICATIONS: These findings suggest that induction of 15-LOX-1-mediated down-regulation of a PPAR-gamma and COX-2 pathway by honokiol may be a promising therapeutic strategy for gastric cancer.

Feng Y, Bai X, Yang Q, et al.
Downregulation of 15-lipoxygenase 2 by glucocorticoid receptor in prostate cancer cells.
Int J Oncol. 2010; 36(6):1541-9 [PubMed] Related Publications
15-lipoxygenase 2 (15-LOX-2) is lost or significantly reduced in prostate cancer. However, the regulation of 15-LOX-2 remains unclear. In this study, we independently cloned the 5' upstream promoter fragments of 15-LOX-2 gene. Target DNA fragments each were cloned into an expression vector containing luciferase reporter gene, which were called LF1(-1533/+87), LF2(-628/+87), LF3(-253/+87), LF4(-157/+87), LF5(-33/+87), LF6(-253/+1), and LF7(-157/+1). Each of these individual promoter fragments was transfected into primary prostate epithelial cells and prostate cancer LNCaP cells. The promoter activity gradually decreased with progressive deletions from LF2 to LF4. A significant drop was noted in the LF5. LF6 and LF7 that did not contain the 87-bp region downstream the transcription start site (TSS) have significant luciferase activities similar to those of corresponding fragments (LF3 and LF4) that contain 87-bp region downstream the TSS. This suggests that the 125-bp region (-157 to -33) of LF4 is critical for the promoter activity of 15-LOX-2 in the primary prostate epithelial cells PrEC and cancer cells LNCaP. Moreover, we discovered a specific glucocorticoid receptor (GR) responsive element (GRE) in this key region. The luciferase activities of the LF4 and LF7 were decreased in the LNCaP cells co-transfected with GR (hGRalpha or hGRbeta) expression vectors. This inhibitory effect is reversed after treatments with dexamethasone or two specific GR inhibitors (siRNAs of GR and RU486). Results from this study suggest a 125-bp region (-157 to -33) is critical for the 15-LOX-2 promoter activity in prostate epithelial cells and cancer cells, which was significantly downregulated by GR via the GRE in this region.

Campbell SE, Musich PR, Whaley SG, et al.
Gamma tocopherol upregulates the expression of 15-S-HETE and induces growth arrest through a PPAR gamma-dependent mechanism in PC-3 human prostate cancer cells.
Nutr Cancer. 2009; 61(5):649-62 [PubMed] Related Publications
Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that gamma-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) gamma, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that gamma-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h. gamma-Tocopherol-mediated growth arrest was demonstrated to be PPAR gamma dependent using the agonist GW9662 and a PPAR gamma dominant negative vector. gamma-tocopherol was shown not to be a direct PPAR gamma ligand, but rather 15-S-HETE (an endogenous PPAR gamma ligand) was upregulated by gamma-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following gamma-tocopherol treatment. Expression of proteins downstream of the PPAR gamma pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFkappa B proteins were found to be downregulated following gamma-tocopherol treatment. These data demonstrate that the growth arrest mediated by gamma-tocopherol follows a PPAR-gamma-dependent mechanism.

Zuo X, Morris JS, Broaddus R, Shureiqi I
15-LOX-1 transcription suppression through the NuRD complex in colon cancer cells.
Oncogene. 2009; 28(12):1496-505 [PubMed] Free Access to Full Article Related Publications
15-Lipoxygenase-1 (15-LOX-1) is transcriptionally silenced in cancer cells, and its transcription reactivation (for example, through histone deacetylase inhibitors (HDACIs)) restores apoptosis to cancer cells. However, the exact mechanism underlying 15-LOX-1 transcription reactivation in cancer cells is still undefined. Therefore, we evaluated the critical mechanisms required for 15-LOX-1 transcription reactivation in colon cancer cells. Specific HDAC1 and HDAC2 inhibition activated 15-LOX-1 transcription. 15-LOX-1 transcription was repressed through transcription repressor complex recruitment in the region of -120 to -391 of the 15-LOX-1 promoter. The nucleosome remodeling and histone deacetylase (NuRD) repression complex was recruited to this region. Depsipeptide significantly reduced the recruitment of NuRD key components (for example, metastasis-associated protein 1 (MTA1) and HDAC1) to the 15-LOX-1 promoter before 15-LOX-1 transcriptional activation. Knock down of NuRD key components (for example, MTA1 and HDAC1) by small interfering RNA (siRNA) activated 15-LOX-1 transcription, as measured by luciferase reporter assays in stably transfected SW480 cells with the 15-LOX-1 promoter construct of the -391, but not the -120 region. Relative to expression in normal tissue, MTA1 expression in colorectal cancer mucosa from colorectal cancer patients was negatively related to 15-LOX-1 expression. Thus, our results show that NuRD contributes to 15-LOX-1 transcription suppression in colon cancer cells and that HDACIs can inhibit NuRD recruitment to a promoter to activate gene transcription, as in the case of 15-LOX-1.

Tang Y, Wang MT, Chen Y, et al.
Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer.
Int J Cancer. 2009; 124(7):1545-51 [PubMed] Free Access to Full Article Related Publications
The enzyme 15-lipoxygenase-2 (15-LOX-2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15(S)-hydroxyeicosatetraenoic acid. Abundantly expressed in normal prostate epithelium but frequently suppressed in the cancerous tissues, 15-LOX-2 has been suggested as a functional suppressor of prostate cancer, but the mechanism(s) involved remains unknown. To study the functional role of 15-LOX-2 in prostate cancer, we expressed 15-LOX-2 as a fusion protein with GFP in DU145 and PC-3 cells and found that 15-LOX-2 increased cell cycle arrest at G0/G1 phase. When injected into athymic nu/nu mice, prostate cancer cells with 15-LOX-2 expression could still form palpable tumors without significant changes in tumorigenicity. But, the tumors with 15-LOX-2 expression grew significantly slower than those derived from vector controls and were kept dormant for a long period of time. Histological evaluation revealed an increase in cell death in tumors derived from prostate cancer cells with 15-LOX-2 expression, while in vitro cell culture conditions, no such increase in apoptosis was observed. Further studies found that the expression of vascular endothelial growth factor A (VEGF-A) was significantly reduced in prostate cancer cells with 15-LOX-2 expression restored. Our studies suggest that 15-LOX-2 suppresses VEGF gene expression and sustains tumor dormancy in prostate cancer. Loss of 15-LOX-2 functionalities, therefore, represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo.

Schain F, Schain D, Mahshid Y, et al.
Differential expression of cysteinyl leukotriene receptor 1 and 15-lipoxygenase-1 in non-Hodgkin lymphomas.
Clin Lymphoma Myeloma. 2008; 8(6):340-7 [PubMed] Related Publications
BACKGROUND: Arachidonic acid metabolites have been suggested to play an important role in carcinogenesis. We have recently reported that the cysteinyl leukotriene receptor 1 (CysLT1) and 15-lipoxygenase-1 (15-LO-1) are expressed by the malignant Hodgkin Reed-Sternberg cells of Hodgkin lymphoma and certain Hodgkin lymphoma cell lines, and that these cells convert arachidonic acid to the novel proinflammatory eoxins.
MATERIALS AND METHODS: The expression of the CysLT1 receptor and 15-LO-1 was investigated in a broad range of non-Hodgkin lymphomas (NHLs) by immunohistochemistry. The functionality of the CysLT1 receptor in primary mediastinal B-cell lymphoma (PMBCL) cell lines was studied by calcium mobilization assays.
RESULTS: Primary mediastinal B-cell lymphoma was the only NHL entity showing tumor cells positive for the CysLT1 receptor (9 of 10 tumors), and the PMBCL cell line Med-B1 expressed functional CysLT1 receptors, responding with a robust calcium signal upon cysteinyl leukotriene challenge. Furthermore, the tumor cells in 1 of 4 T-cell-derived anaplastic large-cell lymphomas, in contrast to all other studied NHLs, strongly expressed 15-LO-1.
CONCLUSION: Among the NHL entities included in this study, the CysLT1 receptor was exclusively expressed by the tumor cells of PMBCL. Thus, this further corroborates the pathologic overlap between PMBCL and classical Hodgkin lymphoma.

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