Document Detail


PTEN induces chemosensitivity in PTEN-mutated prostate cancer cells by suppression of Bcl-2 expression.
MedLine Citation:
PMID:  11495901     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2001-08-08
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  276     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-10-15     Completed Date:  2001-12-04     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38830-6     Citation Subset:  IM    
Affiliation:
Department of Urology Research, Mayo Foundation, Rochester, Minnesota 55905,USA.
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MeSH Terms
Descriptor/Qualifier:
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
Grant Support
ID/Acronym/Agency:
CA15083/CA/NCI NIH HHS; CA91956/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antineoplastic Agents, Phytogenic; 0/Cyclic AMP Response Element-Binding Protein; 0/Enzyme Inhibitors; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Messenger; 0/Tumor Suppressor Proteins; 23214-92-8/Doxorubicin; 57-22-7/Vincristine; 62996-74-1/Staurosporine; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase

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