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

Abstract

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 (eIF2α) 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‐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 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 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‐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.

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

“…Our previous results showed that ERS could regulate the phosphorylation of the radiation‐induced DNA DSB‐related protein ATM in oropharyngeal carcinoma . We hypothesized that XBP1 inhibition could increase radiosensitivity through the activation of DNA DSB formation.…”

“…We previously demonstrated that EGFR confers radioresistance in HPV‐negative human oropharyngeal carcinoma by activating ERS signaling through the double‐stranded RNA‐activated protein kinase‐like ER kinase (PERK) and inositol‐requiring enzyme 1 alpha (IRE1α). Our further research found that PERK confers radioresistance by activating the inflammatory cytokine, nuclear factor‐κB (NF‐κB) . Madhuri C et al showed that IRE1 could induce autophagy in murine macrophage cells under irradiation .…”

“…ATM senses X‐ray‐induced DNA damage and phosphorylation to activate the cell stress response and induce DNA repair or apoptosis . We previously demonstrated that eIF2a silencing confers radiosensitivity through the inhibition of DNA DSB repair and the induction of apoptosis . In addition, we recently showed that EGFR silencing promotes apoptosis and confers radiosensitivity through the inhibition of DNA DSB repair .…”

“…Patients with radiosensitivity were defined as those with lesions that vanished after 6 weeks of radiotherapy and those without tumor or lymph node recurrence within 2 months after radiotherapy. Patients with radioresistance were defined as those with residual lesions after 6 weeks of radiotherapy or with local or regional lymph node recurrence after 2 months of radiotherapy . All recruited patients provided informed consent.…”

Type I interferons and endoplasmic reticulum stress in health and disease

“…Similarly, the IRE1 axis also stimulates NF-κB activity by enforcing proteasomal degradation of IκB (Duran-Aniotz et al, 2017;Rubio et al, 2011;Tam et al, 2012). PERK commands a slightly different pathway for this purpose, it enforces translational inhibition of IκB thereby freeing NF-κB for engaging its transcriptional program (Blais et al, 2006;Halliday et al, 2017;Pytel et al, 2016;Qiao et al, 2017;Tam et al, 2012). Lastly, although ATF6 axis has been shown to influence NF-κB activation yet, the exact mechanism underlying this cascade has not been established (Tam et al, 2018;Yamazaki et al, 2009).…”