Open AccessInterleukin‐6 production mediated by the IRE 1‐ XBP 1 pathway confers radioresistance in human papillomavirus‐negative oropharyngeal carcinoma
Author(s) -
Lyu Xintong,
Zhang Miao,
Li Guangqi,
Cai Yiru,
Li Guang,
Qiao Qiao
Publication year - 2019
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.14094
Subject(s) - radioresistance , cancer research , radiosensitivity , apoptosis , gene silencing , dna damage , biology , medicine , radiation therapy , dna , gene , biochemistry , genetics
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 IRE 1α. In addition, PERK confers radioresistance by activating the inflammatory cytokine NF ‐κB. However, the effect of IRE 1 on radiosensitivity has not yet been fully elucidated. Here, we clarified that IRE 1 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 IRE 1 and XBP 1 increased DNA double‐strand break ( DSB ) and radiation‐induced apoptosis, thereby increasing the radiosensitivity of HPV ‐negative oropharyngeal carcinoma cells. IRE 1‐ XBP 1 silencing also inhibited radiation‐induced IL ‐6 expression at both the RNA and protein levels. The regulatory effect of IRE 1‐ XBP 1 silencing on DNA DSB ‐induced and radiation‐induced apoptosis was inhibited by pretreatment with IL ‐6. These data indicate that IRE 1 regulates radioresistance in HPV ‐negative oropharyngeal carcinoma through IL ‐6 activation, enhancing X‐ray‐induced DNA DSB and cell apoptosis.