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

Abstract

The tumor suppressor gene PTEN (MMAC1/TEP1) is lost frequently in advanced prostate cancer (PCa). However, the function of PTEN in tumorigenesis is not understood fully. In this study, we demonstrate that expression of Bcl-2 in prostate tumors correlates with loss of the PTEN protein. This finding was verified by studies in the PCa cell lines DU145, PC-3, LNCaP, and an androgen-refractory subline of LNCaP. Transient transfection of PTEN into the PTEN-null cells resulted in decreased levels of Bcl-2 mRNA and protein. These effects appear to be mediated at the level of gene transcription, since a Bcl-2 promoter-reporter construct was down-regulated by ectopic expression of PTEN in LNCaP cells. The inhibition of Bcl-2 required the lipid-phosphatase activity of PTEN and was blocked by overexpression of a constitutively active form of Akt. Moreover, the transcription-regulatory protein cAMP-response element-binding protein (CREB) may be involved, since decreased phosphorylation of CREB at Ser(133) was detected following PTEN expression, and ectopic expression of CREB repressed completely the PTEN-induced inhibition of Bcl-2 promoter activity. Furthermore, cotransfection of Bcl-2 and PTEN expression vectors rescued PTEN-induced cell death but not G(1) cell cycle arrest. Finally, forced expression of PTEN sensitized LNCaP cells to cell death induced by staurosporine, doxorubicin, and vincristine, and this chemosensitivity was attenuated by exogenous expression of Bcl-2. Taken together, these data demonstrate that loss of PTEN leads to up-regulation of the bcl-2 gene, thus contributing to survival and chemoresistance of PCa cells. These findings suggest that the PTEN gene and its regulated pathway are potential therapeutic targets in prostate cancer.

• Authors: H Huang, J C Cheville, Y Pan, P C Roche, L J Schmidt, D J Tindall
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 42 Pg. 38830-6 (Oct 19 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11495901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Cyclic AMP Response Element-Binding Protein
• Enzyme Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• Tumor Suppressor Proteins
• Vincristine
• Doxorubicin
• Phosphoric Monoester Hydrolases
• PTEN Phosphohydrolase
• PTEN protein, human
• Staurosporine

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Blotting, Northern
• Blotting, Western
• Cell Separation
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation
• Doxorubicin (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Humans
• Immunoblotting
• Immunohistochemistry
• Male
• Microscopy, Confocal
• PTEN Phosphohydrolase
• Phosphoric Monoester Hydrolases (pharmacology)
• Phosphorylation
• Plasmids (metabolism)
• Promoter Regions, Genetic
• Prostatic Neoplasms (metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, metabolism)
• RNA, Messenger (metabolism)
• Signal Transduction
• Staurosporine (pharmacology)
• Time Factors
• Transcription, Genetic
• Transfection
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (pharmacology)
• Up-Regulation
• Vincristine (pharmacology)