A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum.

Abstract

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.

• Authors: J Lian, X Wu, F He, D Karnak, W Tang, Y Meng, D Xiang, M Ji, T S Lawrence, L Xu
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 18 Issue 1 Pg. 60-71 (Jan 2011) ISSN: 1476-5403 [Electronic] England
• PMID: 20577262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ATG5 protein, human
• Androgens
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Autophagy-Related Protein 5
• BECN1 protein, human
• Beclin-1
• Membrane Proteins
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• bcl-X Protein
• Gossypol

Topics

• Administration, Oral
• Androgens (metabolism)
• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy
• Autophagy-Related Protein 5
• Beclin-1
• Cell Line, Tumor
• Endoplasmic Reticulum (metabolism)
• Female
• Gossypol (therapeutic use)
• Humans
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• Microtubule-Associated Proteins (genetics, metabolism)
• Prostatic Neoplasms (drug therapy)
• Protein Binding
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Transplantation, Heterologous
• bcl-X Protein (metabolism)