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首页> 外文期刊>Journal of Cellular Physiology >Calmodulin protects androgen receptor from calpain-mediated breakdown in prostate cancer cells.
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Calmodulin protects androgen receptor from calpain-mediated breakdown in prostate cancer cells.

机译：钙调蛋白保护雄激素受体calpain-mediated崩溃的前列腺癌细胞。

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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.
机译：虽然雄激素受体的失活(AR) androgen-ablation或长达治疗的一线治疗播散性前列腺癌60多年来,它不是因为castration-resistant治疗前列腺癌细胞保留基于“增大化现实”技术的活动。因此,治疗策略应该包括定点清除的基于“增大化现实”技术的蛋白质。钙调蛋白结合(CaM),因为CaM-binding蛋白质的目标calpain (Cpn)介导的蛋白水解作用,我们研究了凸轮与Cpn的角色在前列腺癌细胞AR崩溃。治疗前列腺癌的细胞分别与anti-CaM药物或calcimycin,从而增加细胞内钙(+ +)和激活尼共,导致最小的基于“增大化现实”技术的故障,结合治疗导致急剧减少基于“增大化现实”技术的蛋白质含量。基于“增大化现实”技术的信使rna没有发生明显的变化水平,建议增加AR蛋白营业额而不是抑制AR信使rna表达式。使敏感AR Cpn-mediated崩溃前列腺癌的细胞。可能性,纯化重组人类AR (rhAR)进行了纯化的蛋白水解作用尼共,增加纯化凸轮孵化了rhAR蛋白水解作用。这些观察表明,AR是尼泊尔共产党目标和AR-bound凸轮扮演重要的角色保护Cpn-mediated崩溃的基于“增大化现实”技术前列腺癌的细胞。一个有趣的可能性,anti-CaM药物结合Cpn-activating代理可以提供治疗前列腺癌的治疗策略癌症,这对经济增长和依赖于基于“增大化现实”技术生存。

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  • 1. PROSTATE CANCER GEN. [P] . 外国专利： ES2190925T3 . 2003-09-01

    机译：prostate cancer gen.

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