脂肪细胞分泌GLN活化mTORC1介导结肠癌腹膜转移后化疗耐受的机制研究

Metabolic reprogramming mediated by activation of adipocyte is causally linked to the tumor progression, while its effect on colon cancer chemotherapy is not well understood. Based on the observation of adipocytes cause colon cancer cell resistance to chemotherapy via Release of Glutamine(Gln), this study aimed to explore the colon cancer chemotherapy- resistance mechanisms and effects of.GS-mediated GLN activation, elucidate the roles of GS in proliferation and apoptosis of colon cancer cells with GS knockout and mTORC1 intervention in colon cancer cell, and reveal the roles of adipocytes GS in the chemotherapy- resistance of colon cancer peritoneal metastasis by subcutaneous or caudal vein xenograft experiments in macrophage GS specific overexpression mice. This study not only can.further explore the molecular mechanism of drug resistance from the point of view of cell metabolism, but also can provide a new strategy to reverse drug resistance and sensitivity to chemotherapy.

脂肪细胞的代谢重编程在结肠癌恶性进展中起重要作用，但其对结肠癌化疗有无影响目前尚不明确。本研究在发现脂肪细胞分泌谷氨酰胺（GLN）的增加引起了结肠癌细胞产生耐药基础上，拟在脂肪细胞系中敲低谷氨酰胺合成酶（GS），联合mTORC1表达干预，解析脂肪细胞GS引起GLN分泌活化mTORC1引起腹膜转移相关结肠癌耐药的机制及效应；阐明脂肪细胞GS对化疗药物处理结肠癌细胞系增殖和凋亡能力的影响；并在脂肪细胞GS基因过表达小鼠模型上，经皮下进行荷瘤实验，揭示脂肪细胞GS对腹膜转移结肠癌细胞化疗耐药的影响。本研究不仅可以从细胞代谢角度进一步探明肿瘤耐药的分子机制，而且可为逆转耐药和化疗增敏提供新的策略。