Hayatine inhibits amino acid-induced mTORC1 activation as a novel mTOR-Rag A/C interaction disruptor

Meiling Lu; Lei Yu; Yanrong Yang; Jiali Zhu; Sujing Qiang; Xinbo Wang; Jia Wang; Xiao Tan; Weifeng Wang; Yue Zhang; Weichao Wang; Jian Xie; Xinyan Chen; Hongbing Wang; Xianghuan Cui; Xin Ge

doi:10.1016/j.bbrc.2021.10.014

Hayatine inhibits amino acid-induced mTORC1 activation as a novel mTOR-Rag A/C interaction disruptor

Biochem Biophys Res Commun. 2021 Oct 21:583:71-78. doi: 10.1016/j.bbrc.2021.10.014. Online ahead of print.

Authors

Meiling Lu¹, Lei Yu², Yanrong Yang², Jiali Zhu², Sujing Qiang¹, Xinbo Wang², Jia Wang², Xiao Tan², Weifeng Wang¹, Yue Zhang¹, Weichao Wang¹, Jian Xie³, Xinyan Chen³, Hongbing Wang³, Xianghuan Cui⁴, Xin Ge⁵

Affiliations

¹ Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, 200072, China.
² Cancer Center, Shanghai Tenth People's Hospital, Medical School of Tongji University, Shanghai, 200072, China.
³ Putuo District People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200060, China.
⁴ Putuo District People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200060, China. Electronic address: cuixh@tongji.edu.cn.
⁵ Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, Medical School of Tongji University, Shanghai, 200072, China. Electronic address: xin.ge@tongji.edu.cn.

PMID: 34735882
DOI: 10.1016/j.bbrc.2021.10.014

Abstract

Abnormal activation of the mechanistic target of rapamycin (mTOR) signaling is commonly observed in many cancers and attracts extensive attention as an oncology drug discovery target, which is encouraged by the success of rapamycin and its analogs (rapalogs) in treatment of mTORC1-hyperactive cancers in both pre-clinic models and clinical trials. However, rapamycin and existing rapalogs have typically short-lasting partial responses due to drug resistance, thereby triggering our interest to investigate a potential mTORC1 inhibitor that is mechanistically different from rapamycin. Here, we report that hayatine, a derivative from Cissampelos, can serve as a potential mTORC1 inhibitor selected from a natural compound library. The unique properties owned by hayatine such as downregulation of mTORC1 activities, induction of mTORC1's translocation to lysosomes followed by autophagy, and suppression on cancer cell growth, strongly emphasize its role as a potential mTORC1 inhibitor. Mechanistically, we found that hayatine disrupts the interaction between mTORC1 complex and its lysosomal adaptor RagA/C by binding to the hydrophobic loop of RagC, leading to mTORC1 inhibition that holds great promise to overcome rapamycin resistance. Taken together, our data shed light on an innovative strategy using structural interruption-based mTORC1 inhibitors for cancer treatment.

Keywords: Hayatine; Rag A/C; Rapamycin; mTOR.