Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.
Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.
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西妥昔单抗抑制 EGFR 后，GRP78 的抑制可消除口咽癌细胞的放射抗性
DOI：
10.1371/journal.pone.0188932
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Qiao Q
中科院分区：
文献类型：
--
作者：
Sun C;Han C;Jiang Y;Han N;Zhang M;Li G;Qiao Q
EGFR特异性mAb西妥昔单抗是口咽癌最有效的治疗方法之一，而单独给予EGFR抑制剂的患者反应是适度的。与放射联合治疗可以通过增加放射敏感性来提高治疗效果，而西妥昔单抗给药后对放射的抵抗限制了其效率。放射和药物可破坏内质网（ER）的稳态，导致内质网应激（ERS），从而引起对放射和药物的抵抗。西妥昔单抗给药后ERS通路是否参与放射抗性尚未报道。在此，我们发现西妥昔单抗可以增加FaDu细胞的放射敏感性，但不能增加Detroit 562细胞的放射敏感性。此外，西妥昔单抗抑制FaDu细胞中ERS信号通路IRE 1 α/ATF 6-GRP 78的辐射诱导激活，而在Detroit 562细胞中不存在这种效应。沉默GRP 78增加了口咽癌细胞的放射敏感性，并抑制了辐射诱导的DNA双链断裂（DSB）修复和自噬。更有趣的是，沉默GRP 78消除了Detroit 562细胞对西妥昔单抗和辐射的抗性，并与西妥昔单抗在增加FaDu细胞的辐射敏感性方面具有协同作用。免疫组化结果显示，GRP 78和EGFR的过度表达与口咽癌患者的预后不良有关（P<0.05）。总体而言，本研究的结果表明，西妥昔单抗抑制EGFR后的放射抗性是由ERS信号通路IRE 1 α/ATF 6-GRP 78介导的。因此，这种抑制不能抑制口咽癌细胞中辐射诱导的DSB修复和自噬，这赋予了对放疗和西妥昔单抗的抗性。这些结果表明，通过抑制无反应口咽癌患者的GRP 78，可以进一步改善放疗和西妥昔单抗的协同作用。
The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB) repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05). Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.
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