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Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells

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Abstract.

The aim of this study was to investigate the contribution of mitochondrial dysfunction to chemoresistance and migration of hepatoma cells. We found that inhibition of mitochondrial respiration and mitochondrial DNA (mtDNA) depletion resulted in induction of amphiregulin (AR) expression in HepG2 cells. Upon oligomycin treatment of HepG2 cells, the cytosolic Ca2+ was significantly raised after 30 min, and the intracellular level of reactive oxygen species (ROS) was elevated 2.2-fold after 4 h. Moreover, the condition medium of oligomycin-treated HepG2 cells was found to stimulate the migration of SK-Hep-1 cells. On the other hand, oligomycin-induced cisplatin-resistance and cell migration of HepG2 cells were attenuated by AR-specific RNA interference (#L-017435, Dharmacon) and a neutralizing antibody (MAB262, R&D Systems), respectively. Together, these findings suggest that mitochondrial dysfunction induced Ca2+ mobilization, and ROS overproduction, which modulated the chemo-resistance and migration of hepatoma cells through the induction and activation of AR.

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  1. C.-J. Chang

    Present address: Department of Food, Health and Nutrition Science, School of Agriculture, Chinese Culture University, Taipei, 111, Taiwan, Republic of China

Authors and Affiliations

  1. Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, 112, Taiwan, Republic of China

    C.-J. Chang, C.-H. Wang, W.-Y. Hung, C.-W. Chi & H.-C. Lee

  2. Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 112, Taiwan, Republic of China

    C.-J. Chang & Y.-H. Wei

  3. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, 112, Taiwan, Republic of China

    P.-H. Yin, D.-M. Yang & C.-W. Chi

  4. Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan, Republic of China

    D.-M. Yang

Authors
  1. C.-J. Chang
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  2. P.-H. Yin
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  3. D.-M. Yang
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  4. C.-H. Wang
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  5. W.-Y. Hung
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  6. C.-W. Chi
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  7. Y.-H. Wei
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  8. H.-C. Lee
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Corresponding authors

Correspondence to Y.-H. Wei or H.-C. Lee.

Additional information

Y.-H. Wei, H.-C. Lee: These authors contribute equally to this work.

Received 02 December 2008; received after revision 16 March 2009; accepted 17 March 2009

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Chang, CJ., Yin, PH., Yang, DM. et al. Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells. Cell. Mol. Life Sci. 66, 1755–1765 (2009). https://doi.org/10.1007/s00018-009-8767-5

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  • DOI: https://doi.org/10.1007/s00018-009-8767-5

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