| Patients with metastatic castrate resistant prostate cancer(m CRPC) are reported to develop resistance to newly FDA-approved anti-androgen receptor(anti-AR) agents; enzalutamide and abiraterone due to the expression of AR splice variant 7(AR-V7). A Phase II clinical trial suggested that these patients are still responsive to Galeterone(Gal), a steroidal antiandrogen that is currently in it s pivotal phase III clinical trial, the first accurate medicine based trial in AR-V7 posit ive m CRPC patients.Since the celastrol chemical structure is similar to Gal, we investigated effects of celastrol against AR-V7 positive prostate cancer cells in this study. Celastrol induced full-length AR protein decrease, consistent with our previous report. In addition, celastrol induced AR-V7 loss in 22Rv1 prostate cancer cells. After celastrol treatment, both the AR-V7 and full length of AR m RNA levels were not decreased, indicating that AR-V7 loss was not due to degradation of AR translat ion as well as AR-V7 splicing. As anti-androgen leads to AR cytosolic localization, we investigated AR-V7 translocation after celastrol treatment. AR-V7 was located in the nucleus, which was not affected by celastrol trea tment. AR-V7 depletion accompanied by activation of apoptosis as shown by cleavage of PARP and Spetrin αII, and apoptotic morphological changes, suggesting that AR-V7 loss was due to caspase activation. When apoptosis were blocked with caspase-3 inhibitor 2-VAD, AR-V7 loss was rescued, demonstrating caspase-3 is responsible for celastrol-induced AR-V7 degradation. Our results suggest a celastrol potential application for the treatment of prostate(PC) cancer patients with AR-V7. |
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