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

叶酸代谢为生物合成和甲基化提供一碳 (1C) 单位，长期以来一直是癌症化疗的目标。线粒体丝氨酸分解代谢被认为是增殖癌细胞中叶酸介导的 1C 单位的唯一贡献者。在这里，我们表明在细胞环境中的生理叶酸水平下，胞质丝氨酸羟甲基转移酶 (SHMT1) 是各种癌症中 1C 单位的主要来源，而线粒体 1C 通量被过度抑制。肿瘤特异性依赖胞质 1C 通量与保留细胞内叶酸的能力差有关，这由SLC19A1的表达决定，SLC19A1编码减少的叶酸载体 (RFC)。我们表明在具有低 RFC 表达的细胞中沉默 SHMT1 会损害嘧啶生物合成和肿瘤生长体内。总体而言，我们的研究结果揭示了癌细胞利用跨肿瘤的细胞溶质与线粒体叶酸循环的主要差异，以及SLC19A1表达作为增加对 SHMT1 依赖的标志物。