Zhao Chenxi, Zhang Tingting, Xue Si-Tu, Zhang Peitao, Wang Feng, Li Yunxuan, Liu Ying, Zhao Luyao, Wu Jie, Yan Yechao, Mao Xiaoyun, Chen Yuping, Yuan Jian, Li Zhuorong, Li Ke
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Cell Metab. 2025 Mar 4;37(3):692-707.e9. doi: 10.1016/j.cmet.2024.09.013. Epub 2024 Oct 22.
Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.
肥胖是乳腺癌预后不良的主要风险因素，但肥胖诱导的肿瘤微环境（TME）代谢物对乳腺癌生长和转移的影响仍不清楚。在此，我们在高脂饮食（HFD）小鼠模型中进行了TME代谢组学分析，发现肥胖加速型乳腺癌的TME中谷胱甘肽（GSH）水平升高。在脂肪细胞而非肿瘤细胞中缺失GSH生物合成的限速酶谷氨酸-半胱氨酸连接酶催化亚基（GCLC），可减少肥胖相关的肿瘤进展。从机制上讲，我们发现GSH进入肿瘤细胞并直接与溶酶体整合膜蛋白2（清道夫受体B类成员2 [SCARB2]）结合，干扰其N端和C端之间的相互作用。反过来，这通过ARF1将mTORC1募集到溶酶体，导致mTOR信号激活。总体而言，我们证明GSH通过作为mTOR信号的激活剂来连接肥胖和乳腺癌进展。靶向GSH/SCARB2/mTOR轴可能使肥胖的乳腺癌患者受益。
