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Deok-Bae Park  (Park DB) 1 Article
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Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells
Deok-Bae Park
Diabetes Metab J. 2015;39(6):518-527.   Published online December 11, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.6.518
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  • 16 Web of Science
  • 17 Crossref
AbstractAbstract PDFPubReader   
Background

Metformin, a well-known anti-diabetic drug, has gained interest due to its association with the reduction of the prevalence of cancer in patients with type 2 diabetes and the anti-proliferative effect of metformin in several cancer cells. Here, we investigated the anti-proliferative effect of metformin with respect to apoptosis and autophagy in H4IIE hepatocellular carcinoma cells.

Methods

H4IIE rat cells were treated with metformin in glucose-free medium for 24 hours and were then subjected to experiments examining the onset of apoptosis and/or autophagy as well as the related signaling pathways.

Results

When H4IIE cells were incubated in glucose-free media for 24 hours, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) reduced the viability of cells. Inhibition of AMP-activated protein kinase (AMPK) by compound C significantly blocked cell death induced by metformin or AICAR. Pro-apoptotic events (nuclear condensation, hydrolysis of intact poly ADP ribose polymerase and caspase-3) were stimulated by metformin and then suppressed by compound C. Interestingly, the formation of acidic intracellular vesicles, a marker of autophagy, was stimulated by compound C. Although the deprivation of amino acids in culture media also induced apoptosis, neither metformin nor compound C affected cell viability. The expression levels of all of the autophagy-related proteins examined decreased with metformin, and two proteins (light chain 3 and beclin-1) were sensitive to compound C. Among the tested inhibitors against MAP kinases and phosphatidylinositol-3-kinase/mammalian target of rapamycin, SB202190 (against p38MAP kinase) significantly interrupted the effects of metformin.

Conclusion

Our data suggest that metformin induces apoptosis, but suppresses autophagy, in hepatocellular carcinoma cells via signaling pathways, including AMPK and p38 mitogen-activated protein kinase.

Citations

Citations to this article as recorded by  
  • Metformin Induces Lipogenesis and Apoptosis in H4IIE Hepatocellular Carcinoma Cells
    Deokbae Park, Sookyoung Lee, Hyejin Boo
    Development & Reproduction.2023; 27(2): 77.     CrossRef
  • Novel phloretin-based combinations targeting glucose metabolism in hepatocellular carcinoma through GLUT2/PEPCK axis of action: in silico molecular modelling and in vivo studies
    Alaa Elmetwalli, Neamat H. Kamosh, Rania El Safty, Amany I. Youssef, Mohammed M. Salama, Khaled M. Abd El-Razek, Tarek El-Sewedy
    Medical Oncology.2023;[Epub]     CrossRef
  • Targeted Pyroptosis Is a Potential Therapeutic Strategy for Cancer
    Hao Wu, Dianlun Qian, Xiangfeng Bai, Shibo Sun, Jayaprakash Narayana Kolla
    Journal of Oncology.2022; 2022: 1.     CrossRef
  • The effects of metformin on autophagy
    Guangli Lu, Zhen Wu, Jia Shang, Zhenxing Xie, Chaoran Chen, Chuning zhang
    Biomedicine & Pharmacotherapy.2021; 137: 111286.     CrossRef
  • Protective Effect of Metformin against Hydrogen Peroxide-Induced Oxidative Damage in Human Retinal Pigment Epithelial (RPE) Cells by Enhancing Autophagy through Activation of AMPK Pathway
    Xia Zhao, Linlin Liu, Yizhou Jiang, Marta Silva, Xuechu Zhen, Wenhua Zheng
    Oxidative Medicine and Cellular Longevity.2020; 2020: 1.     CrossRef
  • Metformin Induces Autophagy via the AMPK-mTOR Signaling Pathway in Human Hepatocellular Carcinoma Cells


    Chun Gao, Long Fang, Hui Zhang, Wei-Shuo Zhang, Xiao-Ou Li, Shi-Yu Du
    Cancer Management and Research.2020; Volume 12: 5803.     CrossRef
  • Metabolomics profiling of metformin-mediated metabolic reprogramming bypassing AMPKα
    Min Yan, Huan Qi, Tian Xia, Xinjie Zhao, Wen Wang, Zhichao Wang, Chang Lu, Zhen Ning, Huan Chen, Tongming Li, Dinesh Singh Tekcham, Xiumei Liu, Jing Liu, Di Chen, Xiaolong Liu, Guowang Xu, Hai-long Piao
    Metabolism.2019; 91: 18.     CrossRef
  • Metformin Induces Oxidative Stress-Mediated Apoptosis without the Blockade of Glycolysis in H4IIE Hepatocellular Carcinoma Cells
    Deokbae Park
    Biological and Pharmaceutical Bulletin.2019; 42(12): 2002.     CrossRef
  • Activation of AMPK prevents monocrotaline-induced pulmonary arterial hypertension by suppression of NF-κB-mediated autophagy activation
    Cui Zhai, Wenhua Shi, Wei Feng, Yanting Zhu, Jian Wang, Shaojun Li, Xin Yan, Qingting Wang, Qianqian Zhang, Limin Chai, Cong Li, Pengtao Liu, Manxiang Li
    Life Sciences.2018; 208: 87.     CrossRef
  • Metformin and epothilone A treatment up regulate pro-apoptotic PARP-1, Casp-3 and H2AX genes and decrease of AKT kinase level to control cell death of human hepatocellular carcinoma and ovary adenocarcinoma cells
    Aneta Rogalska, Barbara Bukowska, Agnieszka Marczak
    Toxicology in Vitro.2018; 47: 48.     CrossRef
  • Quantitative assessment of cell fate decision between autophagy and apoptosis
    Bing Liu, Zoltán N. Oltvai, Hülya Bayır, Gary A. Silverman, Stephen C. Pak, David H. Perlmutter, Ivet Bahar
    Scientific Reports.2017;[Epub]     CrossRef
  • Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients
    Shujuan Ma, Yixiang Zheng, Yanni Xiao, Pengcheng Zhou, Hongzhuan Tan
    Medicine.2017; 96(19): e6888.     CrossRef
  • ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
    Santosh Lamichhane, Tonking Bastola, Ramesh Pariyar, Eun-Sol Lee, Ho-Sub Lee, Dae Lee, Jungwon Seo
    International Journal of Molecular Sciences.2017; 18(3): 674.     CrossRef
  • Metformin represses glucose starvation induced autophagic response in microvascular endothelial cells and promotes cell death
    Samson Mathews Samuel, Suparna Ghosh, Yasser Majeed, Gnanapragasam Arunachalam, Mohamed M. Emara, Hong Ding, Chris R. Triggle
    Biochemical Pharmacology.2017; 132: 118.     CrossRef
  • NHX-5, an Endosomal Na+/H+ Exchanger, Is Associated with Metformin Action
    Jeongho Kim, Hye-Yeon Lee, Jheesoo Ahn, Moonjung Hyun, Inhwan Lee, Kyung-Jin Min, Young-Jai You
    Journal of Biological Chemistry.2016; 291(35): 18591.     CrossRef
  • Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification
    Archana Bhaw-Luximon, Dhanjay Jhurry
    Journal of Cancer Research and Clinical Oncology.2016; 142(10): 2159.     CrossRef
  • Metformina: stary lek w nowej aplikacji
    Anna Dmoszyńska, Monika Podhorecka, Krzysztof Giannopoulos
    Acta Haematologica Polonica.2016; 47(2): 139.     CrossRef

Diabetes Metab J : Diabetes & Metabolism Journal