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.

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 folate 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 drastically 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 expression. 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.

• Authors: Po-Wen Shen, Chun-Te Ho, Shih-Hsin Hsiao, Yu-Ting Chou, Yi-Cheng Chang, Jun-Jen Liu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 16 (Aug 17 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34445544 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Folic Acid
• EGFR protein, human
• ErbB Receptors

Topics

• Apoptosis
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, secondary)
• Cell Movement
• Cell Proliferation
• Cytoplasm (metabolism)
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, genetics)
• Folic Acid (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Tumor Cells, Cultured