近日，中国医学科学院李珂等研究人员合作发现，脂肪细胞衍生的谷胱甘肽通过调控SCARB2-ARF1-mTORC1复合物促进与肥胖相关的乳腺癌。相关论文于2024年10月22日在线发表在《细胞—代谢》杂志上。

研究人员在高脂饮食（HFD）小鼠模型中进行了肿瘤微环境（TME）代谢组分析，发现肥胖加速的乳腺癌TME中谷胱甘肽（GSH）水平升高。删除脂肪细胞中的谷氨酸-半胱氨酸连接酶催化亚基（GCLC），这是GSH生物合成中的限速酶，而不影响肿瘤细胞，进而降低了与肥胖相关的肿瘤进展。

在机制上，研究人员发现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末端和C末端之间的相互作用。这反过来通过ARF1招募mTORC1到溶酶体，导致mTOR信号通路的激活。

总体而言，研究人员证明了GSH通过作为mTOR信号通路的激活剂，连接了肥胖与乳腺癌进展。靶向GSH/SCARB2/mTOR轴可能对肥胖的乳腺癌患者有益。

据了解，肥胖是乳腺癌不良预后的主要风险因素，但肥胖引起的TME代谢物对乳腺癌生长和转移的影响仍不清楚。

附：英文原文

Title: Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex

Author: Chenxi Zhao, Tingting Zhang, Si-tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, Ke Li

Issue&Volume: 2024-10-22

Abstract: 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.

DOI: 10.1016/j.cmet.2024.09.013

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00395-4