Evidence That Arachidonate 15-Lipoxygenase 2 Is a Negative Cell Cycle Regulator in Normal Prostate Epithelial Cells

• Published in: The Journal of biological chemistry Vol. 277; no. 18; pp. 16189 - 16201
• Main Authors: Tang, Shaohua, Bhatia, Bobby, Maldonado, Carlos J, Yang, Peiying, Newman, Robert A, Liu, Junwei, Chandra, Dhyan, Traag, Jeanine, Klein, Russell D, Fischer, Susan M, Chopra, Dharam, Shen, Jianjun, Zhau, Haiyen E, Chung, Leland W K, Tang, Dean G
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 03.05.2002
• Subjects: 15-lipooxygenase; Alternative Splicing; Amino Acid Sequence; Arachidonate 15-Lipoxygenase - chemistry; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Base Sequence; Cell Cycle - physiology; Cell Transformation, Neoplastic; Cells, Cultured; Cloning, Molecular; DNA Primers; Epithelial Cells - cytology; Epithelial Cells - enzymology; Genetic Variation; Genetic Vectors; Humans; Hydroxyeicosatetraenoic Acids - metabolism; Kinetics; Male; Molecular Sequence Data; Prostate - cytology; Prostate - enzymology; Prostatic Neoplasms - enzymology; Recombinant Proteins - metabolism; Reference Values; RNA, Messenger - genetics; Sequence Alignment; Sequence Homology, Amino Acid; Transcription, Genetic
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111936200

15-Lipoxygenase 2 (15-LOX2) is a recently cloned human lipoxygenase that shows tissue-restricted expression in prostate, lung, skin, and cornea. The protein level and enzymatic activity of 15-LOX2 have been shown to be down-regulated in prostate cancers compared with normal and benign prostate tissues. The biological function of 15-LOX2 and the role of loss of 15-LOX2 expression in prostate tumorigenesis, however, remain unknown. We report the cloning and functional characterization of 15-LOX2 and its three splice variants (termed 15-LOX2sv-a, 15-LOX2sv-b, and 15-LOX2sv-c) from primary prostate epithelial cells. Western blotting with multiple primary prostate cell strains and prostate cancer cell lines reveals that the expression of 15-LOX2 is lost in all prostate cancer cell lines, accompanied by decreased enzymatic activity revealed by liquid chromatography/tandem mass spectrometry analyses. Further experiments show that the loss of 15-LOX2 expression results from transcriptional repression caused by mechanism(s) other than promoter hypermethylation or histone deacetylation. Subsequent functional studies indicate the following: 1) the 15-LOX2 product, 15(S)-hydroxyeicosatetraenoic acid, inhibits prostate cancer cell cycle progression; 2) 15-LOX2 expression in primary prostate epithelial cells is inversely correlated with cell cycle; and 3) restoration of 15-LOX2 expression in prostate cancer cells partially inhibits cell cycle progression. Taken together, these results suggest that 15-LOX2 could be a suppressor of prostate cancer development, which functions by restricting cell cycle progression.