SCI
24 May 2019
Methionine is a metabolic dependency of tumor-initiating cells
Wang Z, Yip LY, Lee JHJ, et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 2019;25:825-37.
Wai Leong Tam，Genome Institute of Singapore, Agency for Science, e-mail: bing.lim@merck.com; tamwl@gis.a-star.edu.sg
Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A.
了解細胞代謝對找到針對癌癥代謝途徑的新療法潛能巨大。與正常組織相比，實體腫瘤的細胞的代謝途徑發(fā)生了改變。然而,腫瘤中的癌細胞存在異質(zhì)性,而腫瘤起源細胞(TICs)作為重要的治療靶標,其新陳代謝變化卻不典型。為了了解它們的代謝變化，我們進行了代謝組學和代謝物示蹤分析，結(jié)果顯示TICs具有高甲硫氨酸循環(huán)活性和由MAT2A驅(qū)動的高轉(zhuǎn)甲基化率。
High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.
高甲硫氨酸循環(huán)活性導致甲硫氨酸消耗遠遠超過其再生，導致對外源性的甲硫氨酸需求旺盛。藥物抑制甲硫氨酸循環(huán)，即使是短暫的也足以削弱這些細胞的腫瘤啟動能力。甲硫氨酸循環(huán)通量對癌細胞的表觀遺傳狀態(tài)具有特異性的影響，并驅(qū)動腫瘤的發(fā)生。甲硫氨酸循環(huán)酶在其他腫瘤類型中也有豐富的表達，而MAT2A的表達會影響某些癌細胞對抑制治療的敏感性。
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