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- Title
Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets.
- Authors
Chen, Wan-Jing; Huang, Su-Yu; Chen, Yi-Wen; Liu, Yi-Fang; Huang, Rwei-Fen S.
- Abstract
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.
- Subjects
RISK of metastasis; PROTEIN kinases; FOLIC acid deficiency; RAPAMYCIN; ANIMAL experimentation; LUNG tumors; MTOR inhibitors; METABOLIC disorders; CELLULAR signal transduction; RISK assessment; GENE expression; LACTATES; RESEARCH funding; METFORMIN; MICE; DISEASE risk factors; DISEASE complications
- Publication
Nutrients, 2023, Vol 15, Issue 6, p1514
- ISSN
2072-6643
- Publication type
Article
- DOI
10.3390/nu15061514