Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma
Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma
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富马酸抑制PTEN促进2型乳头状肾细胞癌的肿瘤发生和治疗耐药
DOI：
10.1016/j.molcel.2022.01.029
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发表时间：
2022-04-07
期刊：
影响因子：
16
通讯作者：
Qian, Xu
中科院分区：
文献类型：
--
作者：
Ge, Xin;Li, Mengdie;Qian, Xu
富马酸盐是一种肿瘤代谢物。然而，富马酸盐致瘤的潜在机制仍不清楚。在此，我们以人2型乳头状肾细胞癌（PRCC2）为模型，发现富马酸盐在富马酸水合酶（FH）缺陷的细胞中积累，并抑制PTEN以激活PI3K/AKT信号通路。从机制上讲，富马酸盐在半胱氨酸211（C211）处与PTEN直接反应，形成S -（2 - 琥珀酰）-半胱氨酸。琥珀酰化的C211阻碍了PTEN与细胞膜的连接，从而降低了其对PI3K/AKT通路的抑制作用。在功能上，重新表达野生型FH或PTEN C211S在抑制肿瘤生长以及使PRCC2对舒尼替尼敏感方面，呈现出与AKT抑制剂相似的表型。对临床标本的分析表明，PTEN C211琥珀酰化水平与PRCC2中的AKT激活呈正相关。总之，这些研究结果阐明了富马酸盐在PRCC2中通过对PTEN的直接翻译后修饰所起的非代谢性致癌作用，并进一步揭示了通过联合AKT抑制剂和舒尼替尼治疗对FH缺失患者的潜在分层策略。
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.