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Cyclosporin A activates human hepatocellular carcinoma (HepG2 cells) proliferation: implication of EGFR-mediated ERK1/2 signaling pathway

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Abstract

One of the most common causes of cancer mortality worldwide is hepatocellular carcinoma (HCC). Extracellular signal-regulated kinase (ERK1/2) pathway has been shown to play an important role in the development and progression of HCC. Here, we demonstrate that the immunosuppressive agent cyclosporin A (CsA) has the ability to increase the cellular growth in HCC (HepG2 cells) via activation of ERK1/2 signaling cascade. It was found that ERK1/2 phosphorylation induced by CsA was highly reduced in the presence of the reactive oxygen species (ROS) scavenger polyethylene glycol-superoxide dismutase (PEG-SOD). Furthermore, it was observed that inhibition of metalloproteinase activity using TAPI-2 prevents ERK1/2 activation by CsA. Moreover, a disintegrin and metalloproteinase domain 17 (ADAM-17) activity was found to be critical for ERK phosphorylation by CsA. In addition, CsA-induced ERK phosphorylation was highly reduced in the presence of either neutralizing anti-heparin-binding-epidermal growth factor (HB-EGF) antibody or UO126 (MEK inhibitor). By using the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, it was found that EGFR is critical for ERK phosphorylation induced by CsA. Furthermore, CsA-induced cell proliferation was strongly reduced in the presence of either PEG-SOD or TAPI-2 or neutralizing anti-ADAM17 antibody or neutralizing anti-HB-EGF antibody or AG1478 or UO126. Collectively, these data demonstrate that CsA has the ability to activate ERK1/2 signaling cascade that could be translated into an increase in HepG2 cell proliferation. Furthermore, these data support the role of ROS, ADAM-17, and EGFR in ERK1/2 signaling activation and subsequent cell proliferation induced by CsA in HepG2 cells.

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Authors and Affiliations

  1. Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian-Russian University, Cairo, Egypt

    Mohammed E. Abo-El Fetoh & El-Sayed Akool

  2. Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

    Gouda K. Helal, I. G. Saleh, M. Ewees, Mohamed ElShafey, Mohamed R. Elnagar & El-Sayed Akool

  3. Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt

    Gouda K. Helal

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  1. Mohammed E. Abo-El Fetoh
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Contributions

ESA designed the research. MEAEF, SIG, MRE, and EM performed the research. GKH and MES analyzed the data. ESA wrote the paper. All authors read and approved the final manuscript.

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Correspondence to El-Sayed Akool.

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The experimental procedures were approved by the Institutional Ethics Committee.

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Abo-El Fetoh, M.E., Helal, G.K., Saleh, I.G. et al. Cyclosporin A activates human hepatocellular carcinoma (HepG2 cells) proliferation: implication of EGFR-mediated ERK1/2 signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol 393, 897–908 (2020). https://doi.org/10.1007/s00210-019-01798-w

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