Disruption of cytosolic folate integrity aggravates resistance to epidermal growth factor receptor tyrosine kinase inhibitors and modulates metastatic properties in non-small-cell lung cancer cells
Journal
International Journal of Molecular Sciences
Journal Volume
22
Journal Issue
16
Date Issued
2021
Author(s)
Abstract
Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic fo-late metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1–4 weeks. Our results revealed an increase in NF-κB overexpression–mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can dras-tically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist–treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene ex-pression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
EGFR-TKI; Folate deprivation; Folate integrity; NSCLC; Pro-moted invasiveness; Resistance acquisition
Other Subjects
EGFR protein, human; epidermal growth factor receptor; folic acid; protein kinase inhibitor; apoptosis; cell motion; cell proliferation; cytoplasm; drug resistance; gene expression regulation; genetics; human; lung tumor; metabolism; mutation; non small cell lung cancer; pathology; tumor cell culture; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; Cytoplasm; Drug Resistance, Neoplasm; ErbB Receptors; Folic Acid; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Tumor Cells, Cultured
Publisher
MDPI AG
Type
journal article