EGFR targeting enhances the efficiency of chemotherapy through inhibiting IRE1α-XBP1s pathway in colorectal cancer cells
EGFR targeting enhances the efficiency of chemotherapy through inhibiting IRE1α-XBP1s pathway in colorectal cancer cells
复制标题
EGFR靶向通过抑制结直肠癌细胞中的IRE1 alpha-XBP1s通路提高化疗效率
DOI：
10.7150/jca.44234
复制
发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Zhu, Hongxia
中科院分区：
文献类型：
--
作者：
Huo, Miaomiao;Zhao, Yahui;Zhu, Hongxia
靶向EGFR联合化疗是治疗结直肠癌最有价值的策略之一。然而，耐药性仍然是提高疗效的主要障碍。IRE 1 α-XBP 1 s信号通路在多种恶性肿瘤中被激活，在肿瘤化疗耐药中起重要作用。因此，IRE 1 α-XBP 1 s可能成为克服结直肠癌耐药的潜在靶点。在这项研究中，我们检测了患者癌组织和结直肠癌细胞系中IRE 1 α-XBP 1 s信号转导的激活。在结直肠癌中，IRE 1 α和剪接的XBP 1 s的磷酸化水平异常升高，IRE 1 α-XBP 1 s信号转导激活与EGFR高表达相关。通过EGFR蛋白的过表达或EGF处理的活化，我们发现EGFR活化可以增强IRE 1 α的磷酸化和剪接的XBP 1 s表达。相反，EGFR的抑制降低了IRE 1 α-XBP 1 s信号传导。此外，我们还研究了EGFR调控的下游信号通路。抑制ERK活性可逆转EGFR诱导的IRE 1 α-XBP 1 s活化。Co-IP证实了ERK和IRE 1 α的物理相互作用。细胞生长和集落形成实验表明，抑制IRE 1 α活性可抑制EGFR驱动的结直肠癌细胞增殖。此外，我们发现奥沙利铂可以激活IRE 1 α-XBP 1 s信号传导，并且与西妥昔单抗组合部分逆转了激活。抑制EGFR信号传导可以增强奥沙利铂在体外和体内的疗效。我们的研究结果表明，IRE 1 α RNase活性在结直肠癌中异常升高，EGFR信号可能通过EGFR-MEK-ERK通路激活IRE 1 α/XBP 1 s。IRE 1 α-XBP 1 s通路可能参与EGFR驱动的肿瘤细胞增殖。西妥昔单抗可部分恢复奥沙利铂诱导的IRE 1 α-XBP 1 s活化，从而增强奥沙利铂的抗肿瘤疗效。我们的研究结果宣布了一种新的机制，即靶向EGFR可以抑制化疗诱导的IRE 1 α-XBP 1 s激活，从而提高疗效。
Targeting EGFR combined with chemotherapy is one of the most valuable therapeutic strategies in colorectal cancer. However, resistance remains a major obstacle to improve efficacy. IRE1 alpha-XBP1s signaling pathway is activated in many malignant tumors, and plays important roles in chemoresistance. Therefore, IRE1 alpha-XBP1s might be a potential target to overcome the chemoresistance in colorectal cancer. In this study, we detected the activation of IRE1 alpha-XBP1s signaling in patient cancer tissues and colorectal cancer cell lines. The phosphorylation level of IRE1 alpha and the spliced XBP1s were aberrantly elevated in colorectal cancer, and IRE1 alpha-XBP1s signaling activation was correlated with high EGFR expression. By overexpression of EGFR protein or activation by EGF treatment, we found that EGFR activation could enhance the phosphorylation of IRE1 alpha and spliced XBP1s expression. On the contrary, inhibition of EGFR decreased the IRE1 alpha-XBP1s signaling. Further, we examined the downstream signaling pathways regulated by EGFR. Inhibition of ERK activity could reverse the EGFR induced IRE1 alpha-XBP1s activation. Co-IP confirmed the physical interaction of ERK and IRE1 alpha. Cell growth and colony formation assay showed that the inhibition of IRE1 alpha activity could suppress EGFR driven colorectal cancer cell proliferation. Furthermore, we found that oxaliplatin could activate IRE1 alpha-XBP1 s signaling, and combination with cetuximab partially reversed the activation. Inhibition of EGFR signaling could enhance the efficacy of oxaliplatin in vitro and in vivo. Our results showed that IRE1 alpha RNase activity is aberrantly elevated in colorectal cancer, and EGFR signaling could activate IRE1 alpha/XBP1s possibly through EGFR-MEK-ERK pathway. IRE1 alpha-XBP1s pathway might involve in EGFR driven tumor cell proliferation. Cetuximab could partially recover oxaliplatin-induced IRE1 alpha-XBP1s activation, and therefore enhance the anti-tumor efficacy of oxaliplatin. Our findings declare a new mechanism that targeting EGFR could inhibit chemotherapy-induced IRE1 alpha-XBP1s activation and therefore enhance the efficacy.