Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence.
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.
Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX, USA.
M V
MV
Suraneni
R
R
Schneider-Broussard
J R
JR
Moore
T C
TC
Davis
C J
CJ
Maldonado
H
H
Li
R A
RA
Newman
D
D
Kusewitt
J
J
Hu
P
P
Yang
D G
DG
Tang
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020869:Gene Expression Profiling; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000201:enzymology* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000209:etiology*
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001093:Arachidonate 15-Lipoxygenase