p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways.
Tumor suppressor gene p16 is a cyclin-dependent kinase inhibitor and an important negative cell cycle regulator. The inactivation of p16 appears to be a common event in prostate cancer. Replacement of p16 inhibits prostate tumor cell growth, but the mechanism is not known. Human prostate cancer cell lines PPC-1, which has an inactivated p16, and DU145, which has a nonfunctional retinoblastoma Rb protein (pRb), were used to determine the possible mechanism of p16 mediated growth inhibition. PPC-1 cells treated with 5-aza-2'-deoxycytidine (5-aza-dC), a demethylating agent, induced p16 expression, inhibited cell growth, and induced senescence. Similarly, PPC-1 cells transduced by an adenoviral vector containing the p16 gene (AdRSVp16) produced a p16 protein that suppressed cellular proliferation and induced senescence. Co-staining of AdRSVp16-transduced PPC-1 cells by p16 immunohistochemistry and by beta-galactosidase substrate X-gal showed that the morphologically enlarged cells expressed both p16 and senescence-associated beta-galactosidase. In contrast, AdRSVp16 did not induce senescence in DU145 cells, but did inhibit its growth. However, when wild-type pRb was introduced in DU145 cells, AdRSVp16 was able to induce senescence. Thus, the mechanism by which p16 suppressed prostate cancer was dependent on the pRb functional status of cells whereby p16 caused pRb+ cells to undergo inhibition by senescence, whereas pRb- cells were also inhibited, but not by senescence.
Steiner
M S
MS
University of Tennessee Urologic Research Laboratories, Department of Urology, University of Tennessee-Memphis, Memphis, Tennessee 38163, USA.
Wang
Y
Y
Zhang
Y
Y
Zhang
X
X
Lu
Y
Y
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D000077209:Decitabine; D001374:Azacitidine