以色列理工学院Tomer Shlomi小组研究发现，肿瘤细胞对细胞质或线粒体一碳（1C）合成的依赖取决于叶酸的可及性。该研究于2020年12月15日在线发表于《细胞-代谢》杂志。

研究人员发现在细胞生理叶酸含量情况下，细胞质丝氨酸-羟甲基转移酶（SHMT1）是多种癌症中1C单位的主要来源，而线粒体1C通量往往被过度抑制。肿瘤对细胞质1C通量的依赖性与细胞内叶酸储存能力差有关，这取决于SLC19A1的表达，SLC19A1编码还原叶酸载体（RFC）。研究人员发现在低表达RFC的细胞中沉默SHMT1破坏了嘧啶合成并抑制体内肿瘤生长。

总的来说，该发现揭示了肿瘤细胞对细胞质与线粒体叶酸循环利用方面的主要差异，并且SLC19A1表达是肿瘤细胞对SHMT1依赖性增强的标志。

研究人员表示，叶酸代谢提供了生物合成和甲基化所需的一碳单位，长期以来该代谢通路一直是癌症化疗的靶标。人们认为线粒体丝氨酸分解代谢是增殖型癌细胞中叶酸介导1C单位的唯一来源。

附：英文原文

Title: Tumor Reliance on Cytosolic versus Mitochondrial One-Carbon Flux Depends on Folate Availability

Author: Won Dong Lee, Anna Chiara Pirona, Boris Sarvin, Alon Stern, Keren Nevo-Dinur, Elazar Besser, Nikita Sarvin, Shoval Lagziel, Dzmitry Mukha, Shachar Raz, Elina Aizenshtein, Tomer Shlomi

Issue&Volume: 2020-12-15

Abstract: Folate metabolism supplies one-carbon (1C) units for biosynthesis and methylationand has long been a target for cancer chemotherapy. Mitochondrial serine catabolismis considered the sole contributor of folate-mediated 1C units in proliferating cancercells. Here, we show that under physiological folate levels in the cell environment,cytosolic serine-hydroxymethyltransferase (SHMT1) is the predominant source of 1Cunits in a variety of cancers, while mitochondrial 1C flux is overly repressed. Tumor-specificreliance on cytosolic 1C flux is associated with poor capacity to retain intracellularfolates, which is determined by the expression of SLC19A1, which encodes the reduced folate carrier (RFC). We show that silencing SHMT1 incells with low RFC expression impairs pyrimidine biosynthesis and tumor growth in vivo. Overall, our findings reveal major diversity in cancer cell utilization of the cytosolicversus mitochondrial folate cycle across tumors and SLC19A1 expression as a marker for increased reliance on SHMT1.

DOI: 10.1016/j.cmet.2020.12.002

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30657-4