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.
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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)
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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
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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)
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