Interleukin‐6 production mediated by the IRE1‐XBP1 pathway confers radioresistance in human papillomavirus‐negative oropharyngeal carcinoma

Endoplasmic reticulum stress (ERS) plays a key role in the pathogenesis and development of tumors and protects tumor cells from radiation damage and drug‐induced stress. We previously demonstrated that EGFR confers radioresistance in human papillomavirus (HPV)‐negative human oropharyngeal carcinoma by activating ERS signaling through PERK and IRE1α. In addition, PERK confers radioresistance by activating the inflammatory cytokine NF‐κB. However, the effect of IRE1 on radiosensitivity has not yet been fully elucidated. Here, we clarified that IRE1 overexpression was associated with poor outcome in HPV‐negative patients treated with radiotherapy (P = 0.0001). In addition, a significantly higher percentage of radioresistant HPV‐negative patients than radiosensitive HPV‐negative patients exhibited high IRE expression (66.7% vs 27.8%, respectively; P = 0.001). Silencing IRE1 and XBP1 increased DNA double‐strand break (DSB) and radiation‐induced apoptosis, thereby increasing the radiosensitivity of HPV‐negative oropharyngeal carcinoma cells. IRE1‐XBP1 silencing also inhibited radiation‐induced IL‐6 expression at both the RNA and protein levels. The regulatory effect of IRE1‐XBP1 silencing on DNA DSB‐induced and radiation‐induced apoptosis was inhibited by pretreatment with IL‐6. These data indicate that IRE1 regulates radioresistance in HPV‐negative oropharyngeal carcinoma through IL‐6 activation, enhancing X‐ray‐induced DNA DSB and cell apoptosis.