CRT/ERp57复合体膜转位在子宫内膜癌细胞耐药机制中的作用及临床意义

Immunogenicity of cell death depends on the plasma membrane quantity of calreticulin (CRT), an endoplasmic reticulum (ER) stress protein exposed to the cell membrane after immunogenic treatment. CRT is known to interact in the ER with ERp57, another ER stress protein. CRT and ERp57 are translocated together in the same molecular complex. The exposure of calreticulin (CRT)/ ERp57 complex on the plasma membrane can precede anthracycline-induced apoptosis and is required for cell death to be perceived as immunogenic. Our previous study found that CRT was exposed on the surface of endometrial cancer cell lines. In wide type cell doxorubicin can induce CRT expose to the cell membrane. On the other hand, in resistant cell type the exposure of CRT to the cell membrane by doxorubicin was significantly inhibited compared with wide type cell. Here, we enumerate that doxorubicin may induce endoplasmic reticulum (ER) stress mediated pre-apoptotic CRT/ERp57 exposure in immunogenic of endometrial cancer cell death. In endometrial cancer cells, early activation of the endoplasmic reticulum (ER)-sessile kinase PERK leads to phosphorylation of the translation initiation factor eIF2a, followed by partial activation of caspase-8, caspase-8-mediated cleavage of the ER protein BAP31 and conformational activation of Bax and Bak. Finally, a pool of CRT that has transited the Golgi apparatus is secreted by SNARE-depen-dent exocytosis. By contrast, in doxorubicin-resistant endometrial cancer cells, the immunogenicity of cell death may be abolished, which may be restored by absorbing recombinant CRT to the cell surface.

钙网织蛋白（Calreticulin, CRT)与二硫化物异构酶ERp57复合体从内质网呈递到细胞膜表面介导树突细胞识别和吞噬坏死肿瘤细胞诱发细胞免疫性死亡。肿瘤细胞免疫性死亡的抑制是导致化疗药物耐药的另一重要原因。文献报道蒽环类药物通过刺激内质网应激反应激活eIF2a磷酸化,形成CRT的膜转位效应。本课题前期实验发现多柔比星在野生型子宫内膜癌细胞中可以促进CRT膜表达，而在耐药株中多柔比星诱发CRT的膜表达能力显著降低。基于前期实验的基础本课题将探讨多柔比星在子宫内膜癌细胞中是否可以通过内质网应激反应促进CRT膜表达诱导树突细胞成熟介导肿瘤细胞免疫性死亡，观察在耐多柔比星的子宫内膜癌细胞中CRT膜转位抑制是否和内质网应激反应抑制相关，通过改善CRT膜转位能否有效改善子宫内膜癌对多柔比星的耐药性。为将来临床医师根据患者肿瘤细胞CRT的表达情况进行个体化化疗提供依据和帮助。