A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum.
A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum.
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DOI：
10.1038/cdd.2010.74
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发表时间：
2011-01
影响因子：
12.4
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中科院分区：
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天然BH 3模拟物、Bcl-2的小分子抑制剂（-）-棉酚在正在进行的人类前列腺癌II-III期临床试验中显示出希望。在这里，我们表明，（-）-棉酚优先诱导自噬雄激素非依赖性（AI）前列腺癌细胞，具有高水平的Bcl-2和抗凋亡，在体外和体内，但不是在雄激素依赖性细胞低Bcl-2和敏感的凋亡。Bcl-2抑制剂通过阻断Bcl-2-Beclin 1相互作用，以及下调Bcl-2，上调Beclin 1和激活自噬途径来诱导自噬。（-）-棉酚诱导的自噬是Beclin 1和Atg 5依赖的。我们的研究结果首次表明，（-）-棉酚也可以中断Beclin 1和Bcl-2/Bcl-xL之间的相互作用在内质网，从而释放BH 3-唯一的亲自噬蛋白Beclin 1，这反过来触发自噬级联反应。口服给予（-）-棉酚显著抑制AI前列腺癌异种移植物的生长，这代表了治疗Bcl-2过表达的人前列腺癌难治性前列腺癌的有希望的新方案。我们的数据为Bcl-2抑制剂诱导的细胞死亡模式提供了新的见解，这将有助于通过选择最有可能从Bcl-2靶向分子治疗中获益的患者来合理设计临床试验。
A natural BH3-mimetic, small molecule inhibitor of Bcl-2, (-)-gossypol, shows promise in ongoing Phase II-III clinical trials for human prostate cancer. Here we show that (-)-gossypol preferentially induces autophagy in androgen-independent (AI) prostate cancer cells that have high levels of Bcl-2 and are resistant to apoptosis, both in vitro and in vivo, but not in androgen-dependent cells with low Bcl-2 and sensitive to apoptosis. The Bcl-2 inhibitor induces autophagy via blocking Bcl-2—Beclin1 interaction, together with downregulating Bcl-2, upregulating Beclin1 and activating the autophagic pathway. (-)-Gossypol-induced autophagy is Beclin1- and Atg5-dependent. Our results demonstrate for the first time that (-)-gossypol can also interrupt the interactions between Beclin1 and Bcl-2/Bcl-xL at endoplasmic reticulum, thus releasing the BH3-only pro-autophagic protein Beclin1, which in turn triggers the autophagic cascade. Oral administration of (-)-gossypol significantly inhibited the growth of AI prostate cancer xenografts, representing a promising new regimen for the treatment of human hormone-refractory prostate cancer with Bcl-2 overexpression. Our data provide new insights into the mode of cell death induced by Bcl-2 inhibitors, which would facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl-2-targeted molecular therapy.