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

• Published in: Cell death & disease 2013-02, Vol.4 (2), p.e489-e489
• Main Authors: Cheng, P, Ni, Z, Dai, X, Wang, B, Ding, W, Rae Smith, A, Xu, L, Wu, D, He, F, Lian, J
• Format: Article
• Language: English
• Subjects: 631/67/1059/602; 631/67/395; 631/80/82/39; 692/699/67/1504/1610; Acetylcysteine - pharmacology; Antibodies; Antineoplastic Agents - toxicity; Antioxidants - pharmacology; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; bcl-X Protein - metabolism; Beclin-1; Biochemistry; Biomedical and Life Sciences; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Cyclin D1 - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Gossypol - analogs & derivatives; Gossypol - toxicity; Hep G2 Cells; HMGB1 Protein - metabolism; Humans; Immunology; JNK Mitogen-Activated Protein Kinases - metabolism; Life Sciences; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microtubule-Associated Proteins - metabolism; original-article; Phosphorylation; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2013.17

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.