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TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing

  • Authors:
    • Xin Yao
    • Nasir Roberts
    • Prince Iheukwumere
    • Alana Carmouche
    • Renwei Chen
    • Ma. Carmela Dela Cruz
    • Hector Biliran
  • View Affiliations / Copyright

    Affiliations: Department of Biology, Xavier University of Louisiana, New Orleans, LA 70125, USA, Marine Science Institute, University of California, Santa Barbara, CA 93106, USA, College of Medicine, University of the Philippines Manila, Ermita, Manila 1000, Philippines
    Copyright: © Yao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 36
    |
    Published online on: December 20, 2024
       https://doi.org/10.3892/br.2024.1914
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Abstract

As a putative lung specific oncogene, the transducin‑like enhancer of split 1 (TLE1) corepressor drives an anti‑apoptotic and pro‑epithelial‑mesenchymal transition (EMT) gene transcriptional programs in human lung adenocarcinoma (LUAD) cells, thereby promoting anoikis resistance and tumor aggressiveness. Through its survival‑ and EMT‑promoting gene regulatory programs, TLE1 may impact drug sensitivity and resistance in lung cancer cells. In the present study, a novel function of TLE1 was uncovered as an inhibitor of the antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‑TKI) gefitinib in the human LUAD cell line A549, which exhibits moderate sensitivity to EGFR‑TKI. While upregulation of TLE1 expression potently inhibited the proliferation inhibitory and apoptotic effects of gefitinib in A549 cells, downregulation of endogenous TLE1 in these cells enhanced their sensitivity to gefitinib. In experimentally derived gefitinib‑resistant A549 cells (A549GR) that have acquired EMT, TLE1 expression is upregulated as compared with parental A549 cells, and acute ablation of TLE1 expression is sufficient to partially restore gefitinib sensitivity and attenuate EMT phenotype. Mechanistic studies showed that TLE1 confers gefitinib resistance in A549 cells in part via downregulation of E‑cadherin, a known potentiator of EGFR‑TKI sensitivity and apoptosis induction. Importantly, the TLE1/E‑cadherin transcriptional axis is negatively regulated by gefitinib to trigger apoptosis via the Bcl‑2‑inhibitor of transcription 1 cell death pathway. In conclusion, these results indicate a novel role of TLE1 in modulating EGFR‑TKI sensitivity in lung cancer cells via regulation of E‑cadherin expression, and its upregulation may potentiate EGFR‑TKI resistance in LUAD.
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Copy and paste a formatted citation
Spandidos Publications style
Yao X, Roberts N, Iheukwumere P, Carmouche A, Chen R, Dela Cruz MC and Biliran H: TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing. Biomed Rep 22: 36, 2025.
APA
Yao, X., Roberts, N., Iheukwumere, P., Carmouche, A., Chen, R., Dela Cruz, M.C., & Biliran, H. (2025). TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing. Biomedical Reports, 22, 36. https://doi.org/10.3892/br.2024.1914
MLA
Yao, X., Roberts, N., Iheukwumere, P., Carmouche, A., Chen, R., Dela Cruz, M. C., Biliran, H."TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing". Biomedical Reports 22.3 (2025): 36.
Chicago
Yao, X., Roberts, N., Iheukwumere, P., Carmouche, A., Chen, R., Dela Cruz, M. C., Biliran, H."TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing". Biomedical Reports 22, no. 3 (2025): 36. https://doi.org/10.3892/br.2024.1914
Copy and paste a formatted citation
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Spandidos Publications style
Yao X, Roberts N, Iheukwumere P, Carmouche A, Chen R, Dela Cruz MC and Biliran H: TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing. Biomed Rep 22: 36, 2025.
APA
Yao, X., Roberts, N., Iheukwumere, P., Carmouche, A., Chen, R., Dela Cruz, M.C., & Biliran, H. (2025). TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing. Biomedical Reports, 22, 36. https://doi.org/10.3892/br.2024.1914
MLA
Yao, X., Roberts, N., Iheukwumere, P., Carmouche, A., Chen, R., Dela Cruz, M. C., Biliran, H."TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing". Biomedical Reports 22.3 (2025): 36.
Chicago
Yao, X., Roberts, N., Iheukwumere, P., Carmouche, A., Chen, R., Dela Cruz, M. C., Biliran, H."TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing". Biomedical Reports 22, no. 3 (2025): 36. https://doi.org/10.3892/br.2024.1914
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