2. Academic Validation
  3. Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells

Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells

  • Cell Death Differ. 2021 Apr;28(4):1222-1236. doi: 10.1038/s41418-020-00644-4.
Kang Wang  # 1,  Zhengyang Zhang  # 1,  Hsiang-I Tsai  # 1,  Yanfang Liu 2,  Jie Gao 1,  Ming Wang 1,  Lian Song 1,  Xiongfeng Cao 1,  Zhanxue Xu 3,  Hongbo Chen 3,  Aihua Gong 2,  Dongqing Wang 4,  Fang Cheng 5 6 7,  Haitao Zhu 8
Affiliations

Affiliations

  • 1 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
  • 2 School of Medicine, Jiangsu University, Zhenjiang, 212013, China.
  • 3 School of Pharmaceutical Sciences, SYSU, Shenzhen, 518107, China.
  • 4 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China. wangdongqing71@163.com.
  • 5 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China. chengf9@mail.sysu.edu.cn.
  • 6 School of Pharmaceutical Sciences, SYSU, Shenzhen, 518107, China. chengf9@mail.sysu.edu.cn.
  • 7 Faculty of Science and Engineering, Åbo Akademi University and Turku Bioscience Centre, 20520, Turku, Finland. chengf9@mail.sysu.edu.cn.
  • 8 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China. zhht25@163.com.
  • # Contributed equally.
PMID: 33097833 DOI: 10.1038/s41418-020-00644-4
Abstract

Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for Cancer therapy. Recent advance revealed that the sensitivity to Ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting Ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of Ferroptosis. Mechanistically, Ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key Enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc- inhibition and protected liver and pancreatic Cancer cells from Ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc- activity, triggers Ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of Cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in Ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

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