Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway

Hsin Hwa Tsai, Hong Yue Lai, Yueh Chiu Chen, Chien Feng Li, Huei-Sheng Huang, Hsiao-Sheng Liu, Yau-Sheng Tsai, Ju-Ming Wang

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Metformin, as an AMP-activated protein kinase (AMPK) activator, can activate autophagy. A study showed that metformin decreased the risk of hepatocellular carcinoma (HCC) in diabetic patients. However, the detailed mechanism in the metformin-mediated anticancer effect remains an open question. Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) has been suggested to serve as a tumor suppressor and is responsive to multiple anticancer drugs in HCC. In this study, we found that CEBPD and autophagy are involved in metformin-induced cell apoptosis in Huh7 cells. The underlying mechanisms in this process included a reduction in Src-mediated CEBPD protein degradation and an increase in CEBPDregulated LC3B and ATG3 gene transcription under metformin treatment. We also found that AMPK is involved in metformin-induced CEBPD expression. Combined treatment with metformin and rapamycin can enhance autophagic cell death through the AMPK-dependent and AMPK-independent pathway, respectively. Taken together, we provide a new insight and therapeutic approach by targeting autophagy in the treatment of HCC.

Original languageEnglish
Pages (from-to)13832-13845
Number of pages14
JournalOncotarget
Volume8
Issue number8
DOIs
Publication statusPublished - 2017 Jan 1

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CCAAT-Enhancer-Binding Protein-delta
Metformin
Autophagy
Hepatocellular Carcinoma
Apoptosis
AMP-Activated Protein Kinases
Sirolimus
Therapeutics
Proteolysis
Transcription Factors

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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abstract = "Metformin, as an AMP-activated protein kinase (AMPK) activator, can activate autophagy. A study showed that metformin decreased the risk of hepatocellular carcinoma (HCC) in diabetic patients. However, the detailed mechanism in the metformin-mediated anticancer effect remains an open question. Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) has been suggested to serve as a tumor suppressor and is responsive to multiple anticancer drugs in HCC. In this study, we found that CEBPD and autophagy are involved in metformin-induced cell apoptosis in Huh7 cells. The underlying mechanisms in this process included a reduction in Src-mediated CEBPD protein degradation and an increase in CEBPDregulated LC3B and ATG3 gene transcription under metformin treatment. We also found that AMPK is involved in metformin-induced CEBPD expression. Combined treatment with metformin and rapamycin can enhance autophagic cell death through the AMPK-dependent and AMPK-independent pathway, respectively. Taken together, we provide a new insight and therapeutic approach by targeting autophagy in the treatment of HCC.",
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Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway. / Tsai, Hsin Hwa; Lai, Hong Yue; Chen, Yueh Chiu; Li, Chien Feng; Huang, Huei-Sheng; Liu, Hsiao-Sheng; Tsai, Yau-Sheng; Wang, Ju-Ming.

In: Oncotarget, Vol. 8, No. 8, 01.01.2017, p. 13832-13845.

Research output: Contribution to journalArticle

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AU - Wang, Ju-Ming

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