Although inactivation of the
androgen receptor (AR) by
androgen-ablation or anti-
androgen treatment has been frontline
therapy for disseminated
prostate cancer for over 60 years, it is not curative because
castration-resistant
prostate cancer cells retain AR activity. Therefore, curative strategy should include targeted elimination of AR
protein. Since AR binds to
calmodulin (CaM), and since CaM-
binding proteins are targets of
calpain (Cpn)-mediated proteolysis, we studied the role of CaM and Cpn in AR breakdown in
prostate cancer cells. Whereas the treatment of
prostate cancer cells individually with anti-CaM drug or
calcimycin, which increases intracellular Ca(++) and activates Cpn, led to minimal AR breakdown, combined treatment led to a precipitous decrease in AR
protein levels. This decrease in AR
protein occurred without noticeable changes in AR
mRNA levels, suggesting an increase in AR
protein turnover rather than inhibition of AR
mRNA expression. Thus, CaM inactivation seems to sensitize AR to Cpn-mediated breakdown in
prostate cancer cells. Consistent with this possibility, purified recombinant human AR (rhAR) underwent proteolysis in the presence of purified Cpn, and the addition of purified CaM to the incubation blocked rhAR proteolysis. Together, these observations demonstrate that AR is a Cpn target and AR-bound CaM plays an important role in protecting AR from Cpn-mediated breakdown in
prostate cancer cells. These observations raise an intriguing possibility that anti-CaM drugs in combination with Cpn-activating agents may offer a curative strategy for the treatment of
prostate cancer, which relies on AR for growth and survival.