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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylcysteine / pharmacology
-
Antineoplastic Agents / toxicity*
-
Antioxidants / pharmacology
-
Apoptosis Regulatory Proteins / antagonists & inhibitors
-
Apoptosis Regulatory Proteins / genetics
-
Apoptosis Regulatory Proteins / metabolism*
-
Autophagy / drug effects*
-
Beclin-1
-
Carcinoma, Hepatocellular / metabolism
-
Carcinoma, Hepatocellular / pathology
-
Cell Line, Tumor
-
Cyclin D1 / metabolism
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Gossypol / analogs & derivatives*
-
Gossypol / toxicity
-
HMGB1 Protein / metabolism
-
Hep G2 Cells
-
Humans
-
JNK Mitogen-Activated Protein Kinases / metabolism
-
Liver Neoplasms / metabolism
-
Liver Neoplasms / pathology
-
Membrane Proteins / antagonists & inhibitors
-
Membrane Proteins / genetics
-
Membrane Proteins / 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
Substances
-
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