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

Abstract

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 KB caused by stabilization of IKB. 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. (Cancer Res 2005; 65(11): 4836-43)

Hyperthermia increases the therapeutic efficacy of survivinT34A in mouse tumor models

“…44 On the other hand, hyperthermia is still an angiogenesis inhibitor in the tumor treatments through decreasing the production of tumor-derived vascular endothelial growth factor. 38,39 Thus, the microvessel density in our study was decreased remarkably in tumors of combination treatment when compared with single therapy, which meant the development of angiogenesis was inhibited additionally. For these reasons, the combination treatment in our study has shown a better antitumor effect in vivo than tumor cells in vitro.…”

Androgen receptor and prostate cancer

“…43 Although, not fully understood, blockade of the proteasome pathway by hyperthermia or specific blockers may also have future therapeutic values. 44 Reducing AR protein levels in CaP may become a powerful strategy in CaP treatment. 45 …”

Anticancer effects of 6-o-palmitoyl-ascorbate combined with a capacitive-resistive electric transfer hyperthermic apparatus as compared with ascorbate in relation to ascorbyl radical generation

“…We have studied lipophilic derivatives of Asc including 2-ophosphoryl-6-o-palmitoyl-L-ascorbic acid (Asc2P6-Palm) and found that Asc2P6Palm was advantageous over Asc in terms of anti-metastatic activity (Liu et al 2000(Liu et al , 2003 in addition to antitumor effects Miwa et al 1988). Hyperthermia is the oldest documented tumor treatment modality (Pajonk et al 2005), and is applied in combination with chemotherapy and/or radiotherapy in the clinical setting (Takahashi et al 2002). Though the molecular mechanisms of hyperthermia are not completely understood, it is suggested that inhibition of proteosome function and the relevant signal transduction pathways might be a major factor of heat-induced apoptosis (Pajonk et al 2005).…”

“…Hyperthermia is the oldest documented tumor treatment modality (Pajonk et al 2005), and is applied in combination with chemotherapy and/or radiotherapy in the clinical setting (Takahashi et al 2002). Though the molecular mechanisms of hyperthermia are not completely understood, it is suggested that inhibition of proteosome function and the relevant signal transduction pathways might be a major factor of heat-induced apoptosis (Pajonk et al 2005). The p53-inactivated and pRb-inactivated transfectants showed G2 arrest after hyperthermia and the appearance of a sub-G1 population (van Bree et al 1999).…”