The Mechanism Of XBPls Regulation By EGFR In Colorectal Cancer

Targeting EGFR combined with chemotherapy is a one of the most valuable therapeutic strategy in colorectal cancer.But resistance remains a major obstacle to improve the efficacy.IRE1α-XBP1s signaling pathway is activated in many malignant tumors,and plays important roles in chemoresistance.So,IRE1α-XBP1s might be a potential target to overcome the chemoresistance in colorectal cancer.Protein phosphorylation level of EGFR signaling pathway and IRE 1α were detected by Western Blot,XBP1s expression was evaluated by Real-time PCR.Cell viability and colony formation were performed to explore the roles of cetuximab in HCT116 and SW480 cell lines.HCT 116 Xenograft mice model was used to investigate the efficacy of oxaliplatin.Phosphorylation level of IRE 1α and the spliced XBP1s were aberrantly elevated in colorectal cancer and IRE1α-XBP1s signaling activation was correlated with high EGFR expression.EGFR activation could enhance the phosphorylation of IRE1α and spliced XBPls expression.On the contrary,inhibition of EGFR decreased the IRE1α-XBP1s signaling.Further,Inhibition of ERK activity could reverse the EGFR induced IRE1α-XBP1s activation.Co-IP confirmed the physically interaction of ERK and IRE1α.Inhibition of IRE1α activity could suppress EGFR driven colorectal cancer cell proliferation,Furthermore,oxaliplatin could activate IRE1α-XBP1s signaling,and combination with cetuximab partially reversed the activation.Inhibition of EGFR signaling could enhance the efficacy of oxaliplatin in vitro and in vivo.In summary,IRE1α RNase activity is aberrantly elevated in colorectal cancer,and EGFR signaling could activate IRE1α/XBP1s possibly through EGFR-MEK-ERK pathway.IRE1α-XBP1s pathway might involve in EGFR driven tumor cell proliferation.Cetuximab could partially recover oxaliplatin induced IRE1α-XBP1s activation,and therefore enhance the anti-tumor efficacy of oxaliplatin.Our findings declare a new mechanism that targeting EGFR could inhibit chemotherapy induced IRE1α-XBP1s activation and therefore enhance the efficacy.