A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum.
A natural BH3-mimetic, small-molecule inhibitor of Bcl-2, (-)-gossypol, shows promise in ongoing phase II and III clinical trials for human prostate cancer. In this study 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 (AD) cells with low Bcl-2 and sensitive to apoptosis. The Bcl-2 inhibitor induces autophagy through blocking Bcl-2-Beclin1 interaction, together with downregulating Bcl-2, upregulating Beclin1, and activating the autophagic pathway. The (-)-gossypol-induced autophagy is dependent on Beclin1 and Atg5. Our results show 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 will facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl-2-targeted molecular therapy.
Mesh Terms:
Administration, Oral, Androgens, Animals, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Autophagy, Autophagy-Related Protein 5, Beclin-1, Cell Line, Tumor, Endoplasmic Reticulum, Female, Gossypol, Humans, Male, Membrane Proteins, Mice, Mice, Nude, Microtubule-Associated Proteins, Prostatic Neoplasms, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, RNA Interference, RNA, Small Interfering, Transplantation, Heterologous, bcl-X Protein
Administration, Oral, Androgens, Animals, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Autophagy, Autophagy-Related Protein 5, Beclin-1, Cell Line, Tumor, Endoplasmic Reticulum, Female, Gossypol, Humans, Male, Membrane Proteins, Mice, Mice, Nude, Microtubule-Associated Proteins, Prostatic Neoplasms, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, RNA Interference, RNA, Small Interfering, Transplantation, Heterologous, bcl-X Protein
Cell Death Differ.
Date: Jan. 01, 2011
PubMed ID: 20577262
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