Program in Nutrition and Food Science, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Nutrients. 2023 Mar 21;15(6):1514. doi: 10.3390/nu15061514.
Lactate metabolism plays a pivotal role in cancers but is often overlooked in lung cancer (LC). Folate deficiency has been linked to lung cancer development, but its impact on lactate metabolism and cancer malignancy is unclear. To investigate this, mice were fed either a folate-deficient (FD) or control diet and intrapleurally implanted with lung cancer cells pre-exposed to FD growth medium. Results showed that FD promoted lactate over-production and the formation of tumor oncospheroids (LCSs) with increased metastatic, migration, and invasion potential. Mice implanted with these cells and fed an FD diet developed hyperlactatemia in blood and lungs. This coincided with increased expression of hexokinase 2 (HK2), lactate dehydrogenase (LDH), and decreased expression of pyruvate dehydrogenase (PDH). Pre-treatment of the FD-LCS-implanted mice with the mTORC1 inhibitor, rapamycin, and the anti-metabolic drug metformin abolished FD/LCS-activated mTORC1 and its targets including HIF1α, HK2, LDH, and monocarboxylate transporters (MCT1 and MCT4), which coincided with the reduction in lactate disorders and prevention of LC metastasis. The findings suggest that dietary FD promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets.
乳酸代谢在癌症中起着关键作用，但在肺癌 (LC) 中往往被忽视。叶酸缺乏与肺癌的发展有关，但它对乳酸代谢和癌症恶性程度的影响尚不清楚。为了研究这一点，将小鼠喂食叶酸缺乏 (FD) 或对照饮食，并将预先暴露于 FD 生长培养基的肺癌细胞胸膜内植入。结果表明，FD 促进了乳酸的过度产生，并形成了具有更高转移、迁移和侵袭潜力的肿瘤oncospheroids (LCSs)。用这些细胞植入并喂食 FD 饮食的小鼠在血液和肺部中出现高乳酸血症。这与己糖激酶 2 (HK2)、乳酸脱氢酶 (LDH) 的表达增加和丙酮酸脱氢酶 (PDH) 的表达减少相一致。用 mTORC1 抑制剂雷帕霉素和代谢抑制剂二甲双胍预先治疗 FD-LCS 植入小鼠，可消除 FD/LCS 激活的 mTORC1 及其靶标，包括 HIF1α、HK2、LDH 和单羧酸转运蛋白 (MCT1 和 MCT4)，同时减少乳酸代谢紊乱并预防 LC 转移。研究结果表明，饮食 FD 通过 mTOR 信号转导介导的靶标促进乳酸代谢紊乱，从而使肺癌转移变得敏感。
