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

Po Wen Shen, Chun Te Ho, Shih Hsin Hsiao, Yu Ting Chou, Yi Cheng Chang, Jun Jen Liu

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number8838
JournalInternational journal of molecular sciences
Volume22
Issue number16
DOIs
Publication statusPublished - Aug 2 2021

Keywords

  • EGFR-TKI
  • Folate deprivation
  • Folate integrity
  • NSCLC
  • Pro-moted invasiveness
  • Resistance acquisition

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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