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J. Biol. Chem., Vol. 277, Issue 18, 16189-16201, May 3, 2002
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From the 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.
Evidence That Arachidonate 15-Lipoxygenase 2 Is a Negative
Cell Cycle Regulator in Normal Prostate Epithelial Cells*,
§,§,,,,,,,
,,
Department of Carcinogenesis, the University
of Texas MD Anderson Cancer Center, Science Park Research Division,
Smithville, Texas 78957, the ¶ Department of Experimental
Therapeutics, University of Texas MD Anderson Cancer Center,
Houston, Texas 77030, Institute of Chemical Toxicology, Wayne
State University, Detroit, Michigan 48226, and ** Molecular
Urology and Therapeutics, Department of Urology, Emory University
School of Medicine, Atlanta, Georgia 30322
*
This work was supported in part by NCI Grant CA-90297 (to
D. G. T.) from the National Institutes of Health, Burroughs-Wellcome Fund Award BWF-1122 (to D. G. T.), University of Texas MDACC
Institutional fund (to D. G. T.), National Institutes of Health
Postdoctoral Training Grant T32 CA09480-16 (to C. J. M.), NIEHS
Center Grant ES07784 (to D. G. T.) from the National Institutes of
Health, and NCI Cancer Center Support Grant CA16672 (to R. A. N.)
from the National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org) contains Supplemental Fig. 1.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF468051-AF468054.
§ Both authors contributed equally to this work.
To whom correspondence should be addressed: University of Texas
MD Anderson Cancer Center, Science Park Research Division, Park Rd. 1C,
Smithville, TX 78957. Tel.: 512-237-9575; Fax: 512-237-2475; E-mail: dtang@sprd1.mdacc.tmc.edu.
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