PTEN induces chemosensitivity in PTEN-mutated prostate cancer cells by suppression of Bcl-2 expression

The tumor suppressor gene PTEN (MMAC1/TEP1) is lost frequently in advanced prostate cancer (PCa). However, the function of PTEN in tumorigenesis is no t understood fully. In this study, we demonstrate that expression of Bcl-2 in prostate tumors correlates with loss of the PTEN protein. This finding w as verified by studies in the PCa cell lines DU145, PC-3, LNCaP, and an and rogen-refractory subline of LNCaP. Transient transfection of PTEN into the PTEN-null cells resulted in decreased levels of Bcl-2 mRNA and protein. The se effects appear to be mediated at the level of gene transcription, since a Bcl-2 promoter-reporter construct was down-regulated by ectopic expressio n of PTEN in LNCaP cells. The inhibition of Bcl-2 required the lipid-phosph atase activity of PTEN and was blocked by overexpression of a constitutivel y active form of Akt. Moreover, the transcription-regulatory protein cAMP-r esponse element-binding protein (CREB) may be involved, since decreased pho sphorylation of CREB at Ser(133) was detected following PTEN expression, an d ectopic expression of CREB repressed completely the PTEN-induced inhibiti on of Bcl-2 promoter activity. Furthermore, cotransfection of Bcl-2 and PTE N expression vectors rescued PTEN-induced cell death but not Gl cell cycle arrest. Finally, forced expression of PTEN sensitized LNCaP cells to cell d eath induced by staurosporine, doxorubicin, and vincristine, and this chemo sensitivity was attenuated by exogenous expression of Bcl-2. Taken together , these data demonstrate that loss of PTEN leads to up-regulation of the bc l-2 gene, thus contributing to survival and chemoresistance of PCa cells. T hese findings suggest that the PTEN gene and its regulated pathway are pote ntial therapeutic targets in prostate cancer.