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Article

Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells

  • Authors:
    • Sung-Min Ju
    • Yong-Seok Jo
    • Yoo-Min Jeon
    • Hyun-Ock Pae
    • Dae-Gill Kang
    • Ho-Sub Lee
    • Jun-Sang Bae
    • Byung-Hun Jeon
  • View Affiliations / Copyright

    Affiliations: Department of Pathology, College of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea, Department of Microbiology and Immunology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea , Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea, Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine and Institute for Medical Sciences, Jeonju, Jeonbuk 54907, Republic of Korea
  • Pages: 1957-1964
    |
    Published online on: October 10, 2017
       https://doi.org/10.3892/ijmm.2017.3181
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Abstract

Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of human cancers. However, the nephrotoxicity of cisplatin limits its use as a therapeutic agent. It has been suggested that oxidative stress and p53 activation play important roles in cisplatin-induced nephrotoxicity. It has been demonstrated that the eukaryotic translation initiation factor 2α (eIF2α) may protect HK-2 human renal proximal tubular cells against cisplatin-induced apoptosis through inhibition of reactive oxygen species (ROS)‑mediated p53 activation. The aim of the present study was to investigate the effects of siRNA‑mediated knockdown of the PKR-like endoplasmic reticulum kinase (PERK) gene, which induces the phosphorylation of eIF2α, or Sal003, a selective inhibitor of eIF2α dephosphorylation, on cisplatin‑induced apoptosis in HK-2 cells. Cisplatin induced eIF2α phosphorylation as well as p53 activation. In particular, inhibition of p53 by pifithrin‑α, and upregulation of eIF2α phosphorylation by Sal003, reduced cisplatin-induced apoptosis. Of note, Sal003‑mediated upregulation of eIF2α phosphorylation suppressed cisplatin‑induced p53 activation. Furthermore, reduction of eIF2α phosphorylation by PERK knockdown enhanced cisplatin-induced p53 activation and apoptosis. In addition, the ROS scavenger N-acetyl-L-cysteine inhibited eIF2α phosphorylation as well as p53 activation in HK-2 cells treated with cisplatin, suggesting that oxidative stress induced by cisplatin may lead to apoptosis through p53 activation; furthermore, this stress may confer resistance to apoptosis via eIF2α phosphorylation, which was further supported by the finding that cisplatin‑induced ROS generation was attenuated by Sal003, whereas it was enhanced by PERK knockdown. Furthermore, cisplatin induced the expression of activating transcription factor 4 (ATF4) and heme oxygenase-1 (HO-1) that were enhanced by Sal003 and reduced by PERK knockdown. Taken together, these results suggest that phosphorylation of eIF2α suppresses cisplatin‑induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in HK-2 cells, as ATF4 expression is usually dependent on the phosphorylation of eIF2α and may also transcriptionally induce the expression of HO-1 in response to oxidative stress. Therefore, regulation of eIF2α phosphorylation may play an important role in alleviating cisplatin-induced nephrotoxicity.
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Copy and paste a formatted citation
Spandidos Publications style
Ju S, Jo Y, Jeon Y, Pae H, Kang D, Lee H, Bae J and Jeon B: Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells. Int J Mol Med 40: 1957-1964, 2017.
APA
Ju, S., Jo, Y., Jeon, Y., Pae, H., Kang, D., Lee, H. ... Jeon, B. (2017). Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells. International Journal of Molecular Medicine, 40, 1957-1964. https://doi.org/10.3892/ijmm.2017.3181
MLA
Ju, S., Jo, Y., Jeon, Y., Pae, H., Kang, D., Lee, H., Bae, J., Jeon, B."Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells". International Journal of Molecular Medicine 40.6 (2017): 1957-1964.
Chicago
Ju, S., Jo, Y., Jeon, Y., Pae, H., Kang, D., Lee, H., Bae, J., Jeon, B."Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells". International Journal of Molecular Medicine 40, no. 6 (2017): 1957-1964. https://doi.org/10.3892/ijmm.2017.3181
Copy and paste a formatted citation
x
Spandidos Publications style
Ju S, Jo Y, Jeon Y, Pae H, Kang D, Lee H, Bae J and Jeon B: Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells. Int J Mol Med 40: 1957-1964, 2017.
APA
Ju, S., Jo, Y., Jeon, Y., Pae, H., Kang, D., Lee, H. ... Jeon, B. (2017). Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells. International Journal of Molecular Medicine, 40, 1957-1964. https://doi.org/10.3892/ijmm.2017.3181
MLA
Ju, S., Jo, Y., Jeon, Y., Pae, H., Kang, D., Lee, H., Bae, J., Jeon, B."Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells". International Journal of Molecular Medicine 40.6 (2017): 1957-1964.
Chicago
Ju, S., Jo, Y., Jeon, Y., Pae, H., Kang, D., Lee, H., Bae, J., Jeon, B."Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells". International Journal of Molecular Medicine 40, no. 6 (2017): 1957-1964. https://doi.org/10.3892/ijmm.2017.3181
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