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Submitted on April 18, 2006
Accepted on June 14, 2006
Department of Pathology (C.C., D.C., M.A.J., C.S), and Department of Urology (B.C, F.J.T), Hospitales Universitarios Virgen del Rocío, Seville, Spain 41013
* To whom correspondence should be addressed. E-mail: csaez{at}cica.es.
Androgen-sensitive prostate cancer cells turn androgen-resistant through complex mechanisms that involve dysregulation of apoptosis. We investigated the role of anti-apoptotic Bcl-xL in the progression of prostate cancer, as well as the interactions of Bcl-xL with pro-apoptotic Bax and Bak in androgen-dependent and -independent prostate cancer cells. Immunohistochemical analysis was used to study the expression of Bcl-xL in a series of 139 prostate carcinomas and its association with Gleason grade and time to hormone-resistance. Expression of Bcl-xL was more abundant in prostate carcinomas of higher Gleason grades and significantly associated with the onset of hormone-refractory disease. In vivo interactions of Bcl-xL with Bax or Bak in untreated and camptothecin-treated LNCaP and PC3 cells were investigated by means of co-immunoprecipitation. In the absence of any stimuli, Bcl-xL interacts with Bax and Bak in androgen-independent PC3 cells, but only with Bak in androgen-dependent LNCaP cells. Interactions of Bcl-xL with Bax and Bak were also evidenced in lysates from high-grade prostate cancer tissues. In LNCaP cells treated with camptothecin, an inhibitor of topoisomerase I, the interaction between Bcl-xL and Bak was absent after 36 h, Bcl-xL decreased gradually and Bak increased coincidentally with the progress of apoptosis. These results support a model in which Bcl-xL would exert an inhibitory effect over Bak via heterodimerization. We propose that these interactions may provide mechanisms for suppressing the activity of pro-apoptotic Bax and Bak in prostate cancer cells and that Bcl-xL expression contributes to androgen-resistance and progression of prostate cancer.
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