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J. Biol. Chem., Vol. 276, Issue 42, 38830-38836, October 19, 2001
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From the Departments of 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
Ser133 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
G1 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.
PTEN Induces Chemosensitivity in PTEN-mutated
Prostate Cancer Cells by Suppression of Bcl-2 Expression*
,,, and¶
Urology Research,
¶ Biochemistry and Molecular Biology, and § Laboratory
Medicine and Pathology, Mayo Foundation,
Rochester, Minnesota 55905
*
This work was supported in part by grants from the
T. J. Martell Foundation and NCI, National Institutes of Health
Grants CA15083 and CA91956.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Urology and Biochemistry/Molecular Biology, Mayo Foundation, Rochester, MN 55905. Tel.: 507-284-8139; Fax: 507-284-2384; E-mail:
tindall.donald@mayo.edu.
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