| Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. | |
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MedLine Citation:
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PMID: 21691147 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Sorafenib, a potent multi-kinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanism of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Up-regulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicted that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. Combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC. |
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Authors:
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Ying-Hong Shi; Zhen-Bin Ding; Jian Zhou; Bo Hui; Guo-Ming Shi; Ai-Wu Ke; Xiao-Ying Wang; Zhi Dai; Yuan-Fei Peng; Cheng-Yu Gu; Shuang-Jian Qiu; Jia Fan |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-01 |
Journal Detail:
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Title: Autophagy Volume: 7 ISSN: 1554-8635 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-6-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101265188 Medline TA: Autophagy Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Liver Surgery; Liver Cancer Institute; Zhongshan Hospital; Fudan University; Shanghai, China. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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