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Microenvironment folate stress promotes Warburg‐metabolic switched‐cancer stem cell signaling network and stemness features to mediate invasion and metastasis of lung cancers
Author(s) -
Chen WanJing,
Huang RweiFen S.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.147.7
Subject(s) - cancer stem cell , cancer research , metastasis , biology , sox2 , stem cell , epithelial–mesenchymal transition , cancer cell , warburg effect , lung cancer , cancer , adenocarcinoma , embryonic stem cell , microbiology and biotechnology , pathology , medicine , genetics , gene
Recent advances suggest that cancer stem cells in minute percentages of tumour bulk mediate change of epithelial‐to‐mesenchymal transition (EMT), invasion and metastasis, and drug‐resistance of malignancy tumours. Whether the molecular mechanisms by which metabolic folate stress may promote Warburg‐metabolic switched‐cancer stem cell signaling network and stemness features to mediate invasion and metastasis of lung cancer cells are unknown. Lung embryonic fibroblasts (MRC5), non‐small cell lung cancer cells (NSCLC) including adenocarcinoma (A549, H23) and squamacarcinoma cells (H520) were used as the experiment models to test the hypothesis. As compared with the controls, cultivation of NSCLC cells with clinically low serum folate levels (LF) for 4–8 days gradually and significantly promoted (1) protein expressions of cancer stem cell signature molecules (Shh, Sox2, Oct4, ALDH1A1, HIF‐1 alpha and Foxo3a, (2) expressions of EMT markers (E‐cadherin and vimentin), and (3) morphological EMT alteration. Energetic metabolic switch in the LF‐NSCLC cells, but not the controls, was evident by lactate release, glycolytic enzymes activity and redux status of NADP/NADPH ratios. When replacing the NSCLC cells into the oncogenic suspension medium to mimic human metastatic microenvironment, the LF‐NSCLC, but not the controls, massively transformed to tumour spheroids, developing stemness features. Blockage of mTOR, sonic hedgehog signaling pathways, epigenetic acetylation (Sirt1) and DNA methylation (5AZA) abolished LF‐promoted stem cell signatures, reversed Warburg metabolic switch and eliminated tumour spheroid formations. Antifolate drugs treatment did not completely prevent from LF‐induced tumour spheroid formation. Injection of LF‐NSCLC and control‐NSCLC cells into the NNK‐mutagenized C57BL/6 mice fed with various folate diets exhibited differentially modulations on metastasis tumours. Collectively, metabolic folate stress promotes Warburg‐metabolic switched‐cancer stem cell signaling network and stemness features to mediate invasion and metastasis of lung cancers.