SIRT5在低氧微环境下受GPER介导并通过调控细胞能量代谢促进乳腺癌顺铂耐药发生的分子机制

The incidence of breast cancer in China ranks first among female malignant tumors. In stubborn and refractory patients, chemotherapy is still the preferred treatment. But the occurrence of drug resistance still inhibits the prognosis of patients. Studies have shown that hypoxic microenvironment promotes tumorigenesis and development while suppressing the efficacy of chemotherapy drugs. We found that mitochondrial protein SIRT5 was up-regulated by GPER under hypoxic conditions and confirmed that it acts as an oncogene in breast cancer. SIRT5 inhibited cisplatin-induced breast cancer apoptosis. Since SIRT5 is involved in the regulation of cellular metabolism, we propose that SIRT5 can regulate the sensitivity of breast cancer cell to cisplatin by regulating cellular energy metabolism and mitochondrial function. In the course of the study, we found that GPER promoted YAP into the nucleus and up-regulated SIRT5 by inhibiting the hippo pathway. SIRT5 inhibited AMPK which phosphorylated YAP at S94. We focus on the potential molecular mechanism of YAP-SIRT5-YAP in the formation of positive feedback loop in breast cancer cells. Our research will provide theoretical basis and clinical support for breast cancer sensitivity to cisplatin and gain the opportunity to find pre-evaluation indicators and reversal of drug resistance in cisplatin treatment.

我国乳腺癌发病率跃居女性恶性肿瘤的首位。对于顽固难治性患者，化疗仍是首选的治疗方式，但是耐药成为影响患者疗效的瓶颈。研究指出低氧微环境促进肿瘤发生发展同时抑制化疗药物疗效。我们研究发现线粒体蛋白SIRT5在低氧环境下受GPER介导表达上调，且证实SIRT5在乳腺癌中发挥促癌作用且能够抑制顺铂诱导的乳腺癌凋亡。由于SIRT5参与细胞代谢调控，因此我们提出SIRT5能够通过调节细胞能量代谢、线粒体功能而实现对顺铂敏感性的调节。此外，我们还发现GPER是通过抑制hippo通路促进YAP入核上调SIRT5，而SIRT5能够抑制AMPK促进YAP入核上调代谢、凋亡相关因子表达。因此我们将研究YAP-SIRT5-YAP在乳腺癌细胞中形成positive feedback loop促进顺铂耐药的发生和潜在分子机制，为乳腺癌顺铂治疗寻找预评指标和逆转耐药提供理论依据和临床应用基础。

前期研究发现线粒体蛋白Sirtuin 5（SIRT5）在低氧环境下受GPER介导表达上调，且证实SIRT5在乳腺癌中发挥促癌作用且能够抑制顺铂诱导的乳腺癌凋亡。由于SIRT5参与细胞代谢调控，因此提出SIRT5能够通过调节细胞能量代谢、线粒体功能而实现对顺铂敏感性的调节。此外，还发现GPER是通过抑制hippo通路促进YAP入核上调SIRT5，而SIRT5能够抑制AMPK促进YAP入核上调代谢、凋亡相关因子表达。本项目拟将研究YAP-SIRT5-YAP在乳腺癌细胞中形成正反馈环促进顺铂耐药的发生和潜在分子机制，为乳腺癌顺铂治疗寻找预评指标和逆转耐药提供理论依据和临床应用基础。. SIRT5是NAD+依赖的III类蛋白质脱乙酰基酶，SIRT5参与多种的代谢途径和应激反应途径，在细胞中发挥至关重要的作用。目前，我们已经证实了SIRT5在多种肿瘤中包括乳腺癌、卵巢癌以及前列腺癌等均发挥促癌作用。并且高表达SIRT5在多种肿瘤中与不良预后相关。我们发现SIRT5可以通过调节Nrf2/HO-1通路抑制DNA损伤，从而促进卵巢癌对顺铂的耐药性；在前列腺癌中SIRT5通过ACAT1影响MAPK信号通路，进而影响前列腺癌的增殖、迁移和侵袭能力。本项目研究中，通过对SIRT5深入的研究，不仅可能会成为诊断癌症的新指标而且可能成为新的肿瘤治疗靶点提供相关支持。