Low-folate stress reprograms cancer stem cell-like potentials and bioenergetics metabolism through activation of mTOR signaling pathway to promote in vitro invasion and in vivo tumorigenicity of lung cancers

Chen, Wan-Jing; Huang, Rachel

doi:10.1016/j.jnutbio.2017.10.001

Cited by 23 publications

(19 citation statements)

References 44 publications

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“…Folate is known to play an important role in human health and disease due to its participation in diverse metabolic pathways as well as in the regulation of methylation reactions. Pleiotropic effects of folate in cancer cells have been linked to migratory capacity and invasiveness; though effects may differ by cancer type, stage and molecular subtype [50,61,62]. We have previously shown that folic acid withdrawal resulted in metabolic and bioenergetic changes indicative of a less proliferative as well as less migratory phenotype in mouse TNBC cell lines [50].…”

Section: Discussionmentioning

confidence: 99%

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

et al. 2020

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“…Altered folate metabolism has indeed been implicated in promoting cancer stem cell formation. For example, low folate was linked to pluripotent gene expression via sonic hedgehog or Akt-mTOR-HIF1-FOXO3a pathways in colorectal 30 and lung cancer 31 . Similarly, 5-MethylTetraHydroFolate down-regulation was observed during reprogramming of mouse embryonic fibroblasts (MEFs) into mouse induced pluripotent cells (iPSC) 32 .…”

Section: Discussionmentioning

confidence: 99%

Folate can promote the methionine-dependent reprogramming of glioblastoma cells towards pluripotency

et al. 2019

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Methionine dependency of tumor growth, although not well-understood, is detectable by 11 C-methionine positron emission tomography and may contribute to the aggressivity of glioblastomas (GBM) and meningiomas. Cytosolic folate cycle is required for methionine synthesis. Its dysregulation may influence cell reprogramming towards pluripotency. We evaluated methionine-dependent growth of monolayer (ML) cells and stem cell-like tumor spheres (TS) derived from 4 GBM (U251, U87, LN299, T98G) and 1 meningioma (IOMM-LEE) cell lines. Our data showed that for all cell lines studied, exogenous methionine is required for TS formation but not for ML cells proliferation. Furthermore, for GBM cell lines, regardless of the addition of folate cycle substrates (folic acid and formate), the level of 3 folate isoforms, 5-methytetrahydrofolate, 5,10-methenyltetrahydrofolate, and 10-formyltetrahydrofolate, were all downregulated in TS relative to ML cells. Unlike GBM cell lines, in IOMM-LEE cells, 5-methyltetrahydrofolate was actually more elevated in TS than ML, and only 5,10-methenyltetrahydrofolate and 10-formyltetrahydrofolate were downregulated. The functional significance of this variation in folate cycle repression was revealed by the finding that Folic Acid and 5-methyltetrahydrofolate promote the growth of U251 TS but not IOMM-LEE TS. Transcriptome-wide sequencing of U251 cells revealed that DHFR , SHMT1 , and MTHFD1 were downregulated in TS vs ML, in concordance with the low activity cytosolic folate cycle observed in U251 TS. In conclusion, we found that a repressed cytosolic folate cycle underlies the methionine dependency of GBM and meningioma cell lines and that 5-methyltetrahydrofolate is a key metabolic switch for glioblastoma TS formation. The finding that folic acid facilitates TS formation, although requiring further validation in diseased human tissues, incites to investigate whether excessive folate intake could promote cancer stem cells formation in GBM patients.

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“…For example, low folate (LF) stress reprograms metabolic signals through the activated mTOR signaling pathway, promoting the metastasis and tumorigenicity of lung cancer stem-like cells. 376 However, matcha green tea (MGT), an inhibitor of mTOR, inhibits the proliferation of breast CSCs by targeting mitochondrial metabolism, glycolysis, and multiple cell signaling pathways. 377 A link between the PI3K/ Akt/mTOR pathway and CSCs is clearly evident.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,253

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Low-folate stress reprograms cancer stem cell-like potentials and bioenergetics metabolism through activation of mTOR signaling pathway to promote in vitro invasion and in vivo tumorigenicity of lung cancers

Cited by 23 publications

References 44 publications

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

Folate can promote the methionine-dependent reprogramming of glioblastoma cells towards pluripotency

Targeting cancer stem cell pathways for cancer therapy

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