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Papers In Press, published online ahead of print February 11, 2002
J. Biol. Chem, 10.1074/jbc.M111936200
Submitted on December 14, 2001
Revised on January 22, 2002
Accepted on February 11, 2002

Evidence that Arachidonate 15-lipoxygenase 2 Is a negative cell-cycle regulator in normal prostate epithelial cells

Shaohua Tang, Bobby Bhatia, Carlos J. Maldonado, Peiying Yang, Robert A. Newman, Junwei Liu, Dhyan Chandra, Jeanine Traag, Russell D Klein, Susan M. Fischer, Dharam Chopra, Jianjun Shen, Haiyen Zhau, Leland W.K. Chung, and Dean G. Tang

Carcinogenesis, University of Texas, Smithville, TX 78957

Corresponding Author: dtang{at}sprd1.mdacc.tmc.edu

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 downregulated in prostate cancers compared with normal and benign prostate tissues (Shappell et al., Am. J. Pathol. 155, 235-245, 1999). The biological function of 15-LOX2 and the role of loss of 15-LOX2 expression in prostate tumorigenesis, however, remain unknown. Here 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 reveal that the expression of 15-LOX2 is lost in all prostate cancer cell lines, accompanied by decreased enzymatic activity revealed by LC/MSMS 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 that: 1) the 15-LOX2 product, 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], 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.


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