Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.
Cell Death Dis. 2018 Sep 26;9(10):1005. doi: 10.1038/s41419-018-1063-2.
Cystathionine β-synthase (CBS) is responsible for the first enzymatic reaction in the transsulfuration pathway of sulfur amino acids. The molecular function and mechanism of CBS as well as that of transsulfuration pathway remain ill-defined in cell proliferation and death. In the present study, we designed, synthesized and obtained a bioactive inhibitor CH004 for human CBS, which functions in vitro and in vivo. CH004 inhibits CBS activity, elevated the cellular homocysteine and suppressed the production of hydrogen sulfide in a dose-dependent manner in cells or in vivo. Chemical or genetic inhibition of CBS demonstrates that endogenous CBS is closely coupled with cell proliferation and cell cycle. Moreover, CH004 substantially retarded in vivo tumor growth in a xenograft mice model of liver cancer. Importantly, inhibition of CBS triggers ferroptosis in hepatocellular carcinoma. Overall, the study provides several clues for studying the interplays amongst transsulfuration pathway, ferroptosis and liver cancer.
胱硫醚β合酶（CBS）负责含硫氨基酸转硫途径中的第一个酶促反应。CBS 以及转硫途径的分子功能和机制在细胞增殖和死亡中的定义仍然不明确。在本研究中，我们设计、合成并获得了人 CBS 的生物活性抑制剂 CH004，该抑制剂在体外和体内均有作用。CH004 可抑制 CBS 活性，在细胞或体内以剂量依赖性方式升高细胞同型半胱氨酸并抑制硫化氢的产生。CBS 的化学或遗传抑制表明内源性 CBS 与细胞增殖和细胞周期密切相关。此外，CH004 可显著抑制肝癌异种移植小鼠模型中的体内肿瘤生长。重要的是，CBS 的抑制可引发肝癌中的铁死亡。总的来说，该研究为研究转硫途径、铁死亡和肝癌之间的相互作用提供了一些线索。
