Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
The Third Affiliated Hospital, Guangzhou Medical University, Guangdong, China.
Cell Rep. 2021 Feb 23;34(8):108767. doi: 10.1016/j.celrep.2021.108767.
Although induction of ferroptosis, an iron-dependent form of non-apoptotic cell death, has emerged as an anticancer strategy, the metabolic basis of ferroptotic death remains poorly elucidated. Here, we show that glucose determines the sensitivity of human pancreatic ductal carcinoma cells to ferroptosis induced by pharmacologically inhibiting system xc. Mechanistically, SLC2A1-mediated glucose uptake promotes glycolysis and, thus, facilitates pyruvate oxidation, fuels the tricyclic acid cycle, and stimulates fatty acid synthesis, which finally facilitates lipid peroxidation-dependent ferroptotic death. Screening of a small interfering RNA (siRNA) library targeting metabolic enzymes leads to identification of pyruvate dehydrogenase kinase 4 (PDK4) as the top gene responsible for ferroptosis resistance. PDK4 inhibits ferroptosis by blocking pyruvate dehydrogenase-dependent pyruvate oxidation. Inhibiting PDK4 enhances the anticancer activity of system xc inhibitors in vitro and in suitable preclinical mouse models (e.g., a high-fat diet diabetes model). These findings reveal metabolic reprogramming as a potential target for overcoming ferroptosis resistance.
虽然诱导铁依赖性非凋亡性细胞死亡的铁死亡已成为一种抗癌策略，但铁死亡的代谢基础仍未得到充分阐明。在这里，我们表明葡萄糖决定了人胰腺导管腺癌细胞对通过药理学抑制系统 xc 诱导的铁死亡的敏感性。在机制上，SLC2A1 介导的葡萄糖摄取促进糖酵解，从而促进丙酮酸氧化，为三羧酸循环提供燃料，并刺激脂肪酸合成，最终促进依赖脂质过氧化的铁死亡。针对代谢酶的小干扰 RNA (siRNA) 文库的筛选导致鉴定出丙酮酸脱氢酶激酶 4 (PDK4) 是对铁死亡耐药性负责的首要基因。PDK4 通过阻断丙酮酸脱氢酶依赖性丙酮酸氧化来抑制铁死亡。抑制 PDK4 增强了系统 xc 抑制剂在体外和合适的临床前小鼠模型中的抗癌活性（例如，高脂肪饮食糖尿病模型）。这些发现揭示了代谢重编程作为克服铁死亡耐药性的潜在靶点。
