Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs

  • Authors:
    • Chia-Chi Hsu
    • Ling-Chia Wu
    • Cheng-Yuan Hsia
    • Pen-Hui Yin
    • Chin‑Wen Chi
    • Tien-Shun Yeh
    • Hsin-Chen Lee
  • View Affiliations

  • Published online on: June 30, 2015     https://doi.org/10.3892/or.2015.4092
  • Pages: 1620-1628
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Abstract

Human hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide particularly in Asia. Deregulation of cellular energetics was recently included as one of the cancer hallmarks. Compounds that target the mitochondria in cancer cells were proposed to have therapeutic potential. Biguanide drugs which inhibit mitochondrial complex I and repress mTOR signaling are clinically used to treat type 2 diabetes mellitus patients (T2DM) and were recently found to reduce the risk of HCC in T2DM patients. However, whether alteration of energy metabolism is involved in regulating the sensitivity of HCC to biguanide drugs is still unclear. In the present study, we treated four HCC cell lines with mitochondrial inhibitors (rotenone and oligomycin) and biguanide drugs (metformin and phenformin), and found that the HCC cells which had a higher mitochondrial respiration rate were more sensitive to these treatments; whereas the HCC cells which exhibited higher glycolysis were more resistant. When glucose was replaced by galactose in the medium, the altered energy metabolism from glycolysis to mitochondrial respiration in the HCC cells enhanced the cellular sensitivity to mitochondrial inhibitors and biguanides. The energy metabolism change enhanced AMP-activated protein kinase (AMPK) activation, mTOR repression and downregulation of cyclin D1 and Mcl-1 in response to the mitochondrial inhibitors and biguanides. In conclusion, our results suggest that increased mitochondrial oxidative metabolism upregulates the sensitivity of HCC to biguanide drugs. Enhancing the mitochondrial oxidative metabolism in combination with biguanide drugs may be a therapeutic strategy for HCC.
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September-2015
Volume 34 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Hsu C, Wu L, Hsia C, Yin P, Chi CW, Yeh T and Lee H: Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs. Oncol Rep 34: 1620-1628, 2015
APA
Hsu, C., Wu, L., Hsia, C., Yin, P., Chi, C., Yeh, T., & Lee, H. (2015). Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs. Oncology Reports, 34, 1620-1628. https://doi.org/10.3892/or.2015.4092
MLA
Hsu, C., Wu, L., Hsia, C., Yin, P., Chi, C., Yeh, T., Lee, H."Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs". Oncology Reports 34.3 (2015): 1620-1628.
Chicago
Hsu, C., Wu, L., Hsia, C., Yin, P., Chi, C., Yeh, T., Lee, H."Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs". Oncology Reports 34, no. 3 (2015): 1620-1628. https://doi.org/10.3892/or.2015.4092