The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma [corrected] cells.

Abstract

Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces autophagy in several cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced autophagy through Beclin-1- and reactive oxygen species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced apoptosis and cell killing. Our results show that ApoG2 induced protective autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance cancer cell death through blocking ApoG2-stimulated autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted cancer therapy.

• Authors: P Cheng, Z Ni, X Dai, B Wang, W Ding, A Rae Smith, L Xu, D Wu, F He, J Lian
• Journal: Cell death & disease (Cell Death Dis) Vol. 4 Pg. e489 (Feb 07 2013) ISSN: 2041-4889 [Electronic] England
• PMID: 23392177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antioxidants
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• HMGB1 Protein
• MAP1LC3A protein, human
• Membrane Proteins
• Microtubule-Associated Proteins
• RNA, Small Interfering
• Reactive Oxygen Species
• apogossypolone
• bcl-X Protein
• Cyclin D1
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• Gossypol
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antineoplastic Agents (toxicity)
• Antioxidants (pharmacology)
• Apoptosis Regulatory Proteins (antagonists & inhibitors, genetics, metabolism)
• Autophagy (drug effects)
• Beclin-1
• Carcinoma, Hepatocellular (metabolism, pathology)
• Cell Line, Tumor
• Cyclin D1 (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gossypol (analogs & derivatives, toxicity)
• HMGB1 Protein (metabolism)
• Hep G2 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Liver Neoplasms (metabolism, pathology)
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Phosphorylation
• RNA Interference
• RNA, Small Interfering (metabolism)
• Reactive Oxygen Species (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• bcl-X Protein (metabolism)