硼替佐米通过线粒体Na+/Ca2+交换体调控胞浆Ca2+协同溶瘤麻疹疫苗株抗肺癌策略及其机制研究

具有选择性杀伤肿瘤和可靠安全性的溶瘤麻疹病毒疫苗株(Measles virus Edmonston strain, MV-Edm)已进入多项抗肿瘤临床试验。为增强MV-Edm的抗癌疗效，我们前期通过FDA药物库筛选出蛋白酶体抑制剂硼替佐米（Bortezomib）能增加MV-Edm诱导的合胞体形成，促进病毒复制，显著增强其溶瘤能力。并首次揭示硼替佐米可能通过上调线粒体Na+/Ca2+交换体（NCLX）介导线粒体基质的Ca2+外流致胞浆Ca2+水平上升，从而促进MV-Edm的膜融合蛋白与膜联蛋白Annexin A1的结合，进而增加膜融合而致的合胞体形成，显著增强其抗肿瘤作用。本课题将进一步阐明溶瘤麻疹病毒疫苗株和硼替佐米联合抗瘤的新策略及“NCLX/胞浆Ca2+/MV-Edm膜融合蛋白F/H/Annexin A1复合体/合胞体”的分子轴调控新机制，并为临床提供一种极具潜力的肿瘤生物治疗方案。

With the outstanding capacity of tumor tropism and clinical safety, Measles virus Edmonston strain (MV-Edm) has been approved for several tumor clinical trials. By screening the FDA-approved Drug Library, we found the Bortezomib, a proteasome inhibitor, was capable to enhance the anti-tumor effect of MV-Edm. Further results revealed Bortezomib could facilitate the syncytium formation and promote the viral replication in cancer cells. We hypothesize that Bortezomib cause an mitochondrial Ca2+ efflux by up-regulating the Na+/Ca2+ exchanger NCLX，leading to an increased level of cytosolic Ca2+. The elevated concentration of cytosolic Ca2+ promotes the interaction among the annexin A1 and MV membrane fusion protein F and H, which mediates a efficient fusion pore expansion, therefore the enhanced syncytium formation and tumor killing. This investigation would elucidate the molecular mechanism underlying the combined treatment of oncolytic virus and chemical compound and provide a potential therapeutic strategy for cancer patients.