Phosphorylation of eIF2[alpha] suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells

• Published in: International journal of molecular medicine 2017-12, Vol.40 (6), p.1957
• Main Authors: Ju, Sung-Min, Jo, Yong-Seok, Jeon, Yoo-Min, Pae, Hyun-Ock, Kang, Dae-Gill, Lee, Ho-Sub, Bae, Jun-Sang, Jeon, Byung-Hun
• Format: Article
• Language: English
• Subjects: Care and treatment; Development and progression; Gene expression; Genetic aspects; Health aspects; Kidney diseases; Oxidative stress; Transcription factors
• ISSN: 1107-3756
• DOI: 10.3892/ijmm.2017.3181

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 2[alpha] (eIF2[alpha]) 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 eIF2[alpha], or Sal003, a selective inhibitor of eIF2[alpha] dephosphorylation, on cisplatin-induced apoptosis in HK-2 cells. cisplatin induced eIF2[alpha] phosphorylation as well as p53 activation. In particular, inhibition of p53 by pifIthrin-[alpha], and upregulation of eIF2[alpha] phosphorylation by Sal003, reduced cisplatin-induced apoptosis. of note, Sal003-mediated upregulation of eIF2[alpha] phosphorylation suppressed cisplatin-induced p53 activation. Furthermore, reduction of eIF2[alpha] phosphorylation by PerK knockdown enhanced cisplatin-induced p53 activation and apoptosis. in addition, the roS scavenger N-acetyl-L-cysteine inhibited eIF2[alpha] 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 eIF2[alpha] 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 eIF2[alpha] 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 eIF2[alpha] and may also transcriptionally induce the expression of HO-1 in response to oxidative stress. therefore, regulation of eIF2[alpha] phosphorylation may play an important role in alleviating cispl