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Hyperthermia-Induced Proteasome Inhibition and Loss of Androgen Receptor Expression in Human Prostate Cancer Cells

¹ Department of Radiation Oncology, Experimental Division, David Geffen School of Medicine at UCLA, Los Angeles, California and ² Department of Urology, University Hospital of Münster, Westfälische, Wilhelmsuniversität Münster, Münster, Germany

Requests for reprints: Frank Pajonk, Department of Radiation Oncology, Experimental Division, David Geffen School of Medicine at University of California at Los Angeles, Box 951714, Los Angeles, CA 90095-1714. Phone: 310-825-8589; E-mail: fpajonk{at}mac.com.

Prostate cancer is the second leading cause of death in men in western countries and is usually treated by surgery and/or radiotherapy. More recently, hyperthermia has been introduced into clinical trials investigating a possible effect in the first-line treatment of prostate cancer. However, the molecular mechanisms of hyperthermia are not completely understood. In this study, we investigated the effects of hyperthermia on proteasome function and its significance for signal transduction, cell death and androgen receptor (AR) expression in PC-3, LnCaP, and DU-145 human and TRAMP-C2 murine prostate cancer cells. Hyperthermia caused apoptosis and radiosensitization and decreased 26S proteasome activity in all three human cell lines to about 40% of untreated control cells. 20S proteasome activity was not affected by heat. Heat treatment inhibited constitutive and radiation-induced activation of nuclear factor B caused by stabilization of IB. Although stabilization of AR by proteasome inhibitors has been reported previously, AR protein levels in LnCaP cells decreased dramatically after heat. Our data suggest that inhibition of proteasome function and dependent signal transduction pathways might be a major molecular mechanisms of heat-induced apoptosis and radiosensitization. Hyperthermia abrogates AR expression in androgen-dependent cells and might thus promote malignant progression of prostate cancer.