Open AccessEndoplasmic reticulum stress pathway PERK ‐ eIF 2α confers radioresistance in oropharyngeal carcinoma by activating NF ‐κB
Author(s) -
Qiao Qiao,
Sun Chaonan,
Han Chuyang,
Han Ning,
Zhang Miao,
Li Guang
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13260
Subject(s) - radioresistance , cancer research , endoplasmic reticulum , apoptosis , kinase , phosphorylation , cell cycle , dna damage , unfolded protein response , biology , cell culture , microbiology and biotechnology , dna , biochemistry , genetics
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 ( eIF 2α) may induce aberrant activation of nuclear factor‐κB ( NF ‐κB). Our previous study showed that NF ‐κB conferred radioresistance in lymphoma cells. However, whether PERK ‐ eIF 2α 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 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 eIF 2α increased the radiosensitivity in oropharyngeal carcinoma cells and increased radiation‐induced apoptosis and G2/M phase arrest. PERK ‐ eIF 2α silencing also inhibited radiation‐induced NF ‐κB phosphorylation and increased the DNA double strand break‐related proteins ATM phosphorylation. NF ‐κB activator TNF ‐α and the ATM inhibitor Ku55933 offset the regulatory effect of eIF 2α 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 eIF 2α, enhancing X‐ray‐induced activation of DNA DSB repair, cell apoptosis inhibition and G2/M cell cycle arrest.