INSERM, U848, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, Villejuif, Val de Marne F-94805, France.
Oncogene. 2011 Mar 10;30(10):1147-58. doi: 10.1038/onc.2010.500. Epub 2010 Dec 13.
In contrast to other cytotoxic agents including anthracyclins and oxaliplatin (OXP), cisplatin (CDDP) fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer immune response and hence to amplify its therapeutic efficacy. This failure to induce immunogenic cell death can be attributed to CDDP's incapacity to elicit the translocation of calreticulin (CRT) from the lumen of the endoplasmic reticulum (ER) to the cell surface. Here, we show that, in contrast to OXP, CDDP is unable to activate the protein kinase-like ER kinase (PERK)-dependent phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Accordingly, CDDP also failed to stimulate the formation of stress granules and macroautophagy, two processes that only occur after eIF2α phosphorylation. Using a screening method that monitors the voyage of CRT from the ER lumen to the cell surface, we identified thapsigargin (THAPS), an inhibitor of the sarco/ER Ca(2+)-ATPase as a molecule that on its own does not stimulate CRT exposure, yet endows CDDP with the capacity to do so. The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogenic cell death. Altogether, our results underscore the contribution of the ER stress response to the immunogenicity of cell death.
与其他细胞毒性药物（包括蒽环类药物和奥沙利铂[OXP]）不同，顺铂（CDDP）不能诱导免疫原性细胞死亡，从而刺激抗肿瘤免疫反应，进而增强其治疗效果。这种不能诱导免疫原性细胞死亡的情况可归因于 CDDP 缺乏将钙网蛋白（CRT）从内质网（ER）腔易位到细胞表面的能力。在这里，我们表明，与 OXP 相反，CDDP 不能激活蛋白激酶样 ER 激酶（PERK）依赖性真核翻译起始因子 2α（eIF2α）的磷酸化。因此，CDDP 也未能刺激应激颗粒和巨自噬的形成，这两个过程仅在 eIF2α 磷酸化后才会发生。使用监测 CRT 从 ER 腔到细胞表面的旅程的筛选方法，我们鉴定出 thapsigargin（THAPS），一种肌浆/内质网 Ca(2+)-ATPase 的抑制剂，它本身不会刺激 CRT 暴露，但使 CDDP 具有这种能力。内质网应激诱导剂（如 THAPS 或衣霉素）与 CDDP 的联合有效地诱导 CRT 向质膜易位以及免疫原性细胞死亡，尽管 ER 应激或 CDDP 单独不足以诱导 CRT 暴露和免疫原性细胞死亡。总之，我们的结果强调了内质网应激反应对细胞死亡免疫原性的贡献。
