Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer. © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Fuming Li, Pingyu Liu, Wen Mi, Liucheng Li, Nicole M Anderson, Nicholas P Lesner, Michelle Burrows, Jacqueline Plesset, Ariana Majer, Guanlin Wang, Jinyang Li, Lingzhi Zhu, Brian Keith, M Celeste Simon. Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer. Nature cancer. 2024 Jan;5(1):131-146

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PMID: 38168934

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