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Autophagy inhibition enhances etoposide-induced cell death in human hepatoma G2 cells

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Induction of autophagy usually acts as a survival mechanism of cancer cells in response to chemotherapy. However, the function and molecular mechanism of autophagy in human hepatoma cells under drug treatment is still not clear. To address this issue, we established an experimental model in which HepG2 cells were treated with etoposide, a widely used anticancer agent. We demonstrate the etoposide-induced accumulation of GFP-LC3 dots by fluorescent microscopy, the up-regulation of LC3-II protein expression by Western blotting and the increased number of autophagic vacuoles by electron microscopy, confirming the activation of autophagy by etoposide in HepG2 cells. Inhibition of autophagy by either 3-methyladenine (3MA) or beclin-1 small interfering RNA enhanced etoposide-induced cell death. Furthermore, activation of p53 and AMPK was detected in etoposide-treated cells and inhibition of AMPK triggered apoptosis through suppression of autophagy. On the other hand, inactivation of p53 promoted cell survival through augmentation of autophagy. Collectively, these findings indicate that etoposide-induced autophagy promotes hepatoma cell adaptation and survival, and that autophagy inhibition improves the chemotherapeutic effect of etoposide. Moreover, AMPK activation is clearly associated with etoposide-induced autophagy. We conclude that manipulation of AMPK may be a promising approach of adjuvant chemotherapy for hepatocellular carcinoma.
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Document Type: Research Article

Affiliations: 1: Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China 2: Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, P.R. China

Publication date: January 1, 2011

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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