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Disruption of Cytosolic Folate Integrity Aggravates Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase

Po-Wen Shen1,2, Chun-Te Ho3, Shih-Hsin Hsiao4

  • 1Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112, Taiwan.

International Journal of Molecular Sciences
|August 27, 2021
PubMed

Insights

Folate deficiency in non-small-cell lung cancer (NSCLC) cells promotes metastasis and resistance to EGFR-TKIs by disrupting folate metabolism. Maintaining adequate folic acid levels is crucial for improving patient prognosis during NSCLC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Patients with advanced non-small-cell lung cancer (NSCLC) often experience malnutrition and folate deficiency (FD).
  • Previous research indicated folate deprivation induces drug resistance in hepatocellular carcinoma.
  • The study investigates if disrupted folate metabolism in NSCLC mimics FD-induced metastasis and impacts EGFR-TKI sensitivity.

Purpose of the Study:

  • To assess the impact of disrupted cytosolic folate metabolism on non-small-cell lung cancer (NSCLC) cell metastasis.
  • To determine if folate deficiency or pemetrexed affects NSCLC cell sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
  • To elucidate the role of SLUG in mediating invasiveness and drug resistance in folate-metabolism-disrupted NSCLC cells.

Main Methods:

  • Examined cytosolic folate metabolism disruption in NSCLC cells induced by folate deficiency or pemetrexed over 1-4 weeks.
  • Assessed changes in epithelial-mesenchymal transition (EMT) biomarkers, including N-cadherin, vimentin, MMPs, SOX9, and SLUG.
  • Investigated the effects of SLUG knockdown on invasiveness and erlotinib resistance in folate antagonist-treated NSCLC cells.

Main Results:

  • Disruption of folate metabolism significantly increased EMT biomarkers (N-cadherin, vimentin, MMPs, SOX9, SLUG) mediated by NF-κB overexpression, enhancing NSCLC cell metastatic properties.
  • Cytosolic folate deficiency negatively impacted the cytotoxicity of EGFR-TKIs on NSCLC cells.
  • SLUG knockdown abrogated SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance, and reduced pemetrexed-induced gelatinase activity and MMP gene expression.

Conclusions:

  • Disruption of folate metabolism in NSCLC cells leads to increased metastatic potential and resistance to EGFR-TKIs.
  • Folate metabolism disruption induces significant changes in EMT biomarkers and drug sensitivity.
  • Maintaining adequate folic acid status is critical for improving the prognosis of NSCLC patients undergoing treatment.
Keywords:
EGFR-TKINSCLCfolate deprivationfolate integritypromoted invasivenessresistance acquisition

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