Endoplasmic reticulum stress pathway PERK-eIF2alpha confers radioresistance in oropharyngeal carcinoma by activating NF-kappaB.

Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis and development of malignant tumors, as well as in the regulation of radiochemoresistance and chemoresistance in many malignancies. ERS signaling pathway protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor-2 (eIF2alpha) may induce aberrant activation of nuclear factor-kappaB (NF-kappaB). Our previous study showed that NF-kappaB conferred radioresistance in lymphoma cells. However, whether PERK-eIF2alpha regulates radioresistance in oropharyngeal carcinoma through NF-kappaB 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 the high expression level of PERK in oropharyngeal carcinoma patients resistant to radiation was higher than in patients sensitive to radiation (77.7 and 33.3%, respectively; P < 0.05). Silencing PERK and eIF2alpha increased the radiosensitivity in oropharyngeal carcinoma cells and increased radiation-induced apoptosis and G2/M phase arrest. PERK-eIF2alpha silencing also inhibited radiation-induced NF-kappaB phosphorylation and increased the DNA double strand break-related proteins ATM phosphorylation. NF-kappaB activator TNF-alpha and the ATM inhibitor Ku55933 offset the regulatory effect of eIF2alpha 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 eIF2alpha, enhancing X-ray-induced activation of DNA DSB repair, cell apoptosis inhibition and G2/M cell cycle arrest.