TY - JOUR
T1 - Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells
AU - Bhatia, Bobby
AU - Tang, Shaohua
AU - Yang, Peiying
AU - Doll, Andreas
AU - Aumüeller, Gerhard
AU - Newman, Robert A.
AU - Tang, Dean G.
N1 - Funding Information:
We thank D Chopra and J Rhim for providing cells. This work is supported, in part, by NIH grants CA90297 and AG023374, ACS Grant RSG MGO-105961, DOD grant DAMD17-03-1-0137, University of Texas MDACC PCRP and IRG funds, and NIEHS Center Grant P50 ES07784 (all to DGT). RAN was supported by NCI Cancer Center Support grant CA16672 and P01 CA106451.
PY - 2005/5/19
Y1 - 2005/5/19
N2 - 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, α2β1, 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.
AB - 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, α2β1, 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.
KW - 15-lipoxygenase 2
KW - Cell cycle
KW - Gene regulation
KW - Prostate progenitor cells
KW - Replicative cell senescence
KW - Stem cells
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U2 - 10.1038/sj.onc.1208406
DO - 10.1038/sj.onc.1208406
M3 - Article
C2 - 15750631
AN - SCOPUS:19944389886
SN - 0950-9232
VL - 24
SP - 3583
EP - 3595
JO - Oncogene
JF - Oncogene
IS - 22
ER -