title: Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells.
abstract: 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.
authors.affiliation: Department of Carcinogenesis, the University of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, Texas 78957, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Tang
authors.forename: Bobby
authors.initials: B
authors.lastname: Bhatia
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Maldonado
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Junwei
authors.initials: J
authors.lastname: Liu
authors.forename: Dhyan
authors.initials: D
authors.lastname: Chandra
authors.forename: Jeanine
authors.initials: J
authors.lastname: Traag
authors.forename: Russell D
authors.initials: RD
authors.lastname: Klein
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Dharam
authors.initials: D
authors.lastname: Chopra
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003001:Cloning, Molecular; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology*; D014644:Genetic Variation; D005822:Genetic Vectors; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D011467:Prostate / Q000166:cytology / Q000201:enzymology*; D011471:Prostatic Neoplasms / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; D011994:Recombinant Proteins; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase