Endoplasmic reticulum stress pathway PERK-eIF2α confers radioresistance in oropharyngeal carcinoma by activating NF-κB

Summary

Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis and development of malignant tumours, as well as in the regulation of radio- and chemoresistance in many malignancies. ERS signalling pathway protein kinase RNA-like endoplasmic reticulum kinase (PERK) -eukaryotic initiation factor-2 (eIF2α) may induce aberrant activation of nuclear factor-κB (NF-κB). Our previous study showed that NF-κB confered radioresistance in lymphoma cells. However, whether PERK-eIF2α regulates radioresistance in oropharyngeal carcinoma through NF-κB activation is unknown. Herein, we showed that PERK overexpression correlated with a poor prognosis for patients with oropharyngeal carcinoma (p<0.01). Meanwhile, the percentage of high expression level of PERK in oropharyngeal carcinoma patients resistant to radiation was higher than those in patients sensitive to radiation (77.7% and 33.3%, respectively, p<0.05). Silencing PERK and eIF2α increased the radiosensitivity in oropharyngeal carcinoma cells and increased radiation-induced apoptosis and G2/M phase arrest. PERK-eIF2α silencing also inhibited radiation-induced NF-κB phosphorylation and increased the DNA double strand break (DSB) -related proteins ATM phosphorylation. NF-κB activator TNF-α and the ATM inhibitor Ku55933 offset the regulatory effect of eIF2α on the expression of radiation-induced cell apoptosis-related proteins and the G2/M phase arrest-related proteins. These data indicate that PERK regulates radioresistance in oropharyngeal carcinoma through NF-kB activation mediated phosphorylation of eIF2α, enhancing X-ray induced activation of DNA DSB repair, cell apoptosis inhibition, and G2/M cell cycle arrest.

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