Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN.
Understanding the functional roles of the molecular alterations that are involved in the oncogenesis of prostate cancer, the second most frequent cause of cancer-related deaths among men in the United States is the focus of numerous investigations. To examine the possible significance of alterations associated with the tumor suppressor gene, MMAC/PTEN, in prostate carcinoma, the biological and biochemical effects of MMAC/PTEN expression were examined in LNCaP cells, which are devoid of a functional gene product. Acute expression of MMAC/PTEN via an adenoviral construct resulted in a dose-dependent and specific inhibition of Akt/PKB activation, consistent with the phosphatidylinositol phosphatase activity of MMAC/PTEN. MMAC/PTEN expression induced apoptosis in LNCaP cells, although to a lesser extent than that observed with p53 via an adenoviral construct. However, MMAC/PTEN expression produced a growth inhibition that was significantly greater than that achieved with p53. Overexpression of Bcl-2 in LNCaP cells blocked MMAC/PTEN- and p53-induced apoptosis but not the growth-suppressive effects of MMAC/ PTEN, suggesting that the growth regulatory effects of MMAC/PTEN involve multiple pathways. These studies further implicate the loss of MMAC/PTEN as a significant event in prostate cancer and suggest that reintroduction of MMAC/PTEN into deficient prostate cancer cells may have therapeutic implications.
Davies
M A
MA
Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Koul
D
D
Dhesi
H
H
Berman
R
R
McDonnell
T J
TJ
McConkey
D
D
Yung
W K
WK
Steck
P A
PA
D017209:Apoptosis / Q000502:physiology*; D029681:Arabidopsis Proteins; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010940:Plant Proteins / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D029681:Arabidopsis Proteins; D010940:Plant Proteins; D015221:Potassium Channels; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C074500:AKT1 protein, Arabidopsis; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human