title: Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer.
abstract: 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.
authors.affiliation: Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA.
authors.forename: Mahipal V
authors.initials: MV
authors.lastname: Suraneni
authors.affiliation: Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Moore
authors.affiliation: Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA.
authors.forename: Dingxiao
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Badeaux
authors.affiliation: Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Macaluso
authors.affiliation: Division of Pharmacology and Toxicology; College of Pharmacy; The University of Texas at Austin; Austin, TX USA.
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.affiliation: Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Kusewitt
authors.affiliation: Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA; Cancer Stem Cell Institute; Research Center for Translational Medicine; Shanghai East Hospital; Tongji University School of Medicine; Shanghai, China.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D000071183:Autophagy-Related Proteins; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011470:Prostatic Hyperplasia / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000071183:Autophagy-Related Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C407704:RB1CC1 protein, human; D025521:Tumor Suppressor Proteins; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase; D011505:Protein-Tyrosine Kinases
keywords: 15-lipoxygenase-2; RB1CC1; c-Myc; prostate cancer; senescence; tumor suppression
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