Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Mol Cell. 2022 Apr 7;82(7):1249-1260.e7. doi: 10.1016/j.molcel.2022.01.029. Epub 2022 Feb 24.
Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.
延胡索酸是一种致癌代谢物。然而，延胡索酸发挥致癌作用的机制尚不清楚。在这里，我们利用人 2 型乳头状肾细胞癌（PRCC2）作为模型，表明延胡索酸在缺乏延胡索酸水合酶（FH）的细胞中积累，并抑制 PTEN 以激活 PI3K/AKT 信号通路。在机制上，延胡索酸直接在半胱氨酸 211（C211）处与 PTEN 反应，形成 S-(2-琥珀酰)-半胱氨酸。琥珀酰化的 C211 阻止了 PTEN 与细胞膜的连接，从而降低了其对 PI3K/AKT 通路的抑制作用。功能上，野生型 FH 或 PTEN C211S 的重新表达可模拟 AKT 抑制剂在抑制肿瘤生长和使 PRCC2 对舒尼替尼敏感方面的作用。对临床标本的分析表明，PRCC2 中 PTEN C211 琥珀酰化水平与 AKT 激活呈正相关。总的来说，这些发现阐明了延胡索酸通过对 PTEN 的直接翻译后修饰在 PRCC2 中发挥非代谢性致癌作用，并进一步揭示了通过组合 AKTi 和舒尼替尼治疗 FH 缺失患者的潜在分层策略。
