Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell Cycle. 2014;13(11):1798-810. doi: 10.4161/cc.28757. Epub 2014 Apr 14.

Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer.

Author information

1
Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA.
2
Division of Pharmacology and Toxicology; College of Pharmacy; The University of Texas at Austin; Austin, TX USA.
3
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.

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.

KEYWORDS:

15-lipoxygenase-2; RB1CC1; c-Myc; prostate cancer; senescence; tumor suppression

PMID:
24732589
PMCID:
PMC4111726
DOI:
10.4161/cc.28757
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Taylor & Francis Icon for PubMed Central
    Loading ...
    Support Center