Regulation of Akt PKB activity, cellular growth, and apoptosis in prostatecarcinoma cells by MMAC PTEN

Understanding the functional roles of the molecular alterations that are in volved in the oncogenesis of prostate cancer, the second most frequent caus e of cancer-related deaths among men in the United States is the focus of n umerous investigations. To examine the possible significance of alterations associated with the tumor suppressor gene, MMAC/PTEN, in prostate carcinom a, the biological and biochemical effects of MMAC/PTEN expression were exam ined in LNCaP cells, which are devoid of a functional gene product, Acute e xpression of MMAC/PTEN via an adenoviral construct resulted in a dose-depen dent and specific inhibition of Akt/PKB activation, consistent with the pho sphatidylinositol phosphatase activity of MMAC/PTEN, MMAC/PTEN expression i nduced apoptosis in LNCaP cells, although to a lesser extent than that obse rved with p53 via an adenoviral construct. However, MMAC/PTEN expression pr oduced a growth inhibition that was significantly greater than that achieve d with p53, Overexpression of Bcl-2 in LNCaP cells blocked MMAC/PTEN- and p 53-induced apoptosis but not the growth-suppressive effects of MMAC/PTEN, s uggesting that the growth regulatory effects of MMAC/PTEN involve multiple pathways, These studies further implicate the loss of MMAC/PTEN as a signif icant event in prostate cancer and suggest that reintroduction of MMAC/PTEN into deficient prostate cancer cells may have therapeutic implications.