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Originally published In Press as doi:10.1074/jbc.M202852200 on June 25, 2002

J. Biol. Chem., Vol. 277, Issue 36, 32510-32515, September 6, 2002
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Raloxifene, a Mixed Estrogen Agonist/Antagonist, Induces Apoptosis through Cleavage of BAD in TSU-PR1 Human Cancer Cells*

Heung Tae KimDagger , Byung Chul KimDagger , Isaac Yi KimDagger §, Mizuko MamuraDagger , Do Hwan SeongDagger , Ja-June JangDagger , and Seong-Jin KimDagger

From the Dagger  Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892 and § Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030

Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta . Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10-9 to 10-6 M range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-XL following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.

* 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: Laboratory of Cell Regulation and Carcinogenesis, NCI, Bldg. 41, Rm. C629, 41 Library Dr., MSC 5055, National Institutes of Health, Bethesda, MD 20892-5055. Tel.: 301-496-8350; Fax: 301-496-8395; E-mail: Kims@mail.nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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