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PMID: 20514017 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence.

Oncogene ·Vol. 29 ·No. 30 ·2010-07-29 ·Pages 4261-75

Suraneni MV, Schneider-Broussard R, Moore JR, Davis TC, Maldonado CJ, Li H, Newman RA, Kusewitt D, Hu J, Yang P, Tang DG

Abstract

15-Lipoxygenase 2 (15-LOX2), a lipid-peroxidizing enzyme, is mainly expressed in the luminal compartment of the normal human prostate, and is often decreased or lost in prostate cancer. Previous studies from our lab implicate 15-LOX2 as a functional tumor suppressor. To better understand the biological role of 15-LOX2 in vivo, we generated prostate-specific 15-LOX2 transgenic mice using the ARR2PB promoter. Unexpectedly, transgenic expression of 15-LOX2 or 15-LOX2sv-b, a splice variant that lacks arachidonic acid-metabolizing activity, resulted in age-dependent prostatic hyperplasia and enlargement of the prostate. Prostatic hyperplasia induced by both 15-LOX2 and 15-LOX2sv-b was associated with an increase in luminal and Ki-67(+) cells; however, 15-LOX2-transgenic prostates also showed a prominent increase in basal cells. Microarray analysis revealed distinct gene expression profiles that could help explain the prostate phenotypes. Strikingly, 15-LOX2, but not 15-LOX2sv-b, transgenic prostate showed upregulation of several well-known stem or progenitor cell molecules including Sca-1, Trop2, p63, Nkx3.1 and Psca. Prostatic hyperplasia caused by both 15-LOX2 and 15-LOX2sv-b did not progress to prostatic intraprostate neoplasia or carcinoma and, mechanistically, prostate lobes (especially those of 15-LOX2 mice) showed a dramatic increase in senescent cells as revealed by increased SA-betagal, p27(Kip1) and heterochromatin protein 1gamma staining. Collectively, our results suggest that 15-LOX2 expression in mouse prostate leads to hyperplasia and also induces cell senescence, which may, in turn, function as a barrier to tumor development.

MeSH Terms
Animals Arachidonate 15-Lipoxygenase/genetics,physiology Cell Proliferation Cellular Senescence Cyclin-Dependent Kinase Inhibitor p27 Gene Expression Profiling Intracellular Signaling Peptides and Proteins/analysis Ki-67 Antigen/analysis Male Mice Mice, Transgenic Prostate/enzymology,pathology Prostatic Hyperplasia/etiology
Chemicals
CDKN1B protein, human Intracellular Signaling Peptides and Proteins Ki-67 Antigen Mki67 protein, mouse Cyclin-Dependent Kinase Inhibitor p27 Arachidonate 15-Lipoxygenase
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Suraneni M V
Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX, USA.
Schneider-Broussard R
Moore J R
Davis T C
Maldonado C J
Li H
Newman R A
Kusewitt D
Hu J
Yang P
Tang D G
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2010.197
Published
2010-07-29
Epub
2010-00-31
Pages
4261-75
Language
English
Region
England
NLM ID
8711562
PMCID
PMC3042242
Subset
IM
Grants
NIA NIH HHS · R01 AG023374-03 · United States
NIA NIH HHS · R01-AG023374 · United States
NCI NIH HHS · P30 CA016672 · United States
NIA NIH HHS · R01 AG023374-01A1 · United States
NIEHS NIH HHS · R01 ES015888-02 · United States
NIA NIH HHS · R01 AG023374-02 · United States
NIA NIH HHS · R01 AG023374 · United States
NIEHS NIH HHS · R21-ES015893-01A1 · United States
NIEHS NIH HHS · P30 ES007784 · United States
NIEHS NIH HHS · ES07784 · United States
NIEHS NIH HHS · R21 ES015893 · United States
NIEHS NIH HHS · R01 ES015888-03 · United States
NIEHS NIH HHS · R21 ES015893-02 · United States
NIEHS NIH HHS · R01-ES01588 · United States
NIEHS NIH HHS · R01 ES015888-04 · United States
NIEHS NIH HHS · R01 ES015888-01 · United States
NIA NIH HHS · R01 AG023374-05 · United States
NIEHS NIH HHS · R01 ES015888 · United States
NIA NIH HHS · R01 AG023374-04 · United States
NIEHS NIH HHS · R21 ES015893-01A1 · United States
External Links
PubMed source DOI: 10.1038/onc.2010.197 PMC Full Text View journal details
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