Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells.
Normal human prostatic (NHP) epithelial cells undergo senescence in vitro and in vivo, but little is known about the tissue-specific molecular mechanisms. Here we first characterize young primary NHP cells as CK5(+)/CK18(+) intermediate basal cells that also express several other putative stem/progenitor cell markers including p63, CD44, alpha2beta1, and hTERT. When cultured in serum- and androgen-free medium, NHP cells gradually lose the expression of these markers, slow down in proliferation, and enter senescence. Several pieces of evidence implicate 15-lipoxygenase 2 (15-LOX2), a molecule with a restricted tissue expression and most abundantly expressed in adult human prostate, in the replicative senescence of NHP cells. First, the 15-LOX2 promoter activity and the mRNA and protein levels of 15-LOX2 and its multiple splice variants are upregulated in serially passaged NHP cells, which precede replicative senescence and occur in a cell-autonomous manner. Second, all immortalized prostate epithelial cells and prostate cancer cells do not express 15-LOX2. Third, PCa cells stably transfected with 15-LOX2 or 15-LOX2sv-b, a splice variant that does not possess arachidonate-metabolizing activity, show a passage-related senescence-like phenotype. Fourth, infection of early-passage NHP cells with retroviral vectors encoding 15-LOX2 or 15-LOX2sv-b induces partial cell-cycle arrest and big and flat senescence-like phenotype. Finally, 15-LOX2 protein expression in human prostate correlates with age. Together, these data suggest that 15-LOX2 may represent an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence.
Bhatia
Bobby
B
Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, 1808 Park Rd. 1C, Smithville, TX 78957, USA.
Tang
Shaohua
S
Yang
Peiying
P
Doll
Andreas
A
Aumüeller
Gerhard
G
Newman
Robert A
RA
Tang
Dean G
DG
D000293:Adolescent; D000328:Adult; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D016922:Cellular Senescence / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000166:cytology* / Q000201:enzymology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D001093:Arachidonate 15-Lipoxygenase