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Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells in vitro

  • Authors:
    • Hsin-Yi Chiu
    • Chi-Ming Chiang
    • Szu-Peng Yeh
    • De-Shien Jong
    • Leang-Shin Wu
    • Hung-Chang Liu
    • Chih-Hsien Chiu
  • View Affiliations / Copyright

    Affiliations: Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan, R.O.C., Division of Thoracic Surgery, Department of Surgery, MacKay Memorial Hospital (Tamsui Branch), New Taipei City 251, Taiwan, R.O.C.
    Copyright: © Chiu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 206
    |
    Published online on: September 8, 2020
       https://doi.org/10.3892/ol.2020.12069
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Abstract

Patients with lung cancer harboring activating epidermal growth factor (EGFR) mutations and pre‑existing diabetes have been demonstrated to exhibit poor responses to first‑line EGFR‑tyrosine kinase inhibitor (TKI) therapy. Strategies for the management of acquired resistance to EGFR‑TKIs in patients with advanced non‑small cell lung cancer (NSCLC) are urgently required. Only a limited number of studies have been published to date on the effects of insulin on EGFR‑TKI resistance in NSCLC. Hence, the aim of the present study was to investigate the roles of hyperinsulinemia and hyperglycemia in mediating gefitinib resistance in NSCLC cells with activating EGFR mutations. In the present study, the HCC4006 cell line, which harbors EGFR mutations, was co‑treated with gefitinib and long‑acting insulin glargine. Whether hyperinsulinemia is able to mediate EGFR‑TKI resistance in the NSCLC cell line harboring activating EGFR mutations was also investigated, and the possible underlying mechanisms responsible for these actions were explored. The inhibition of cell proliferation, and the potential mechanism of gefitinib resistance, were examined using an MTS proliferation assay and western blot analysis, and through the transfection of siRNAs. Whether the inhibition of AKT is able to overcome EGFR‑TKI resistance induced by long‑acting insulin was also investigated. The results obtained suggested that hyperinsulinemia induced by glargine upregulated NSCLC cell proliferation and survival, and induced gefitinib resistance. By contrast, the morphology and proliferation of the cells in a medium containing a 2‑fold concentration of glucose were not significantly affected. Gefitinib resistance induced by hyperinsulinemia may have been mediated via the phosphoinositide 3‑kinase (PI3K)/AKT pathway rather than the mitogen‑activated protein kinase extracellular signal regulated kinase (MAPK/ERK) pathway. AKT serine/threonine kinase 1 knockdown by siRNA rescued the gefitinib resistance that was induced by hyperinsulinemia. In conclusion, hyperinsulinemia, but not hyperglycemia, was identified to cause the development of gefitinib resistance in NSCLC cells with activating EGFR mutations. However, additional studies are required to investigate strategies, such as co targeting hyperinsulinemia and the PI3K/AKT pathway, for overcoming EGFR‑TKI resistance in patients with NSCLC.
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Copy and paste a formatted citation
Spandidos Publications style
Chiu H, Chiang C, Yeh S, Jong D, Wu L, Liu H and Chiu C: Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>. Oncol Lett 20: 206, 2020.
APA
Chiu, H., Chiang, C., Yeh, S., Jong, D., Wu, L., Liu, H., & Chiu, C. (2020). Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>. Oncology Letters, 20, 206. https://doi.org/10.3892/ol.2020.12069
MLA
Chiu, H., Chiang, C., Yeh, S., Jong, D., Wu, L., Liu, H., Chiu, C."Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>". Oncology Letters 20.5 (2020): 206.
Chicago
Chiu, H., Chiang, C., Yeh, S., Jong, D., Wu, L., Liu, H., Chiu, C."Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>". Oncology Letters 20, no. 5 (2020): 206. https://doi.org/10.3892/ol.2020.12069
Copy and paste a formatted citation
x
Spandidos Publications style
Chiu H, Chiang C, Yeh S, Jong D, Wu L, Liu H and Chiu C: Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>. Oncol Lett 20: 206, 2020.
APA
Chiu, H., Chiang, C., Yeh, S., Jong, D., Wu, L., Liu, H., & Chiu, C. (2020). Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>. Oncology Letters, 20, 206. https://doi.org/10.3892/ol.2020.12069
MLA
Chiu, H., Chiang, C., Yeh, S., Jong, D., Wu, L., Liu, H., Chiu, C."Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>". Oncology Letters 20.5 (2020): 206.
Chicago
Chiu, H., Chiang, C., Yeh, S., Jong, D., Wu, L., Liu, H., Chiu, C."Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitor via the PI3K/AKT pathway in non‑small cell lung cancer cells<em> in&nbsp;vitro</em>". Oncology Letters 20, no. 5 (2020): 206. https://doi.org/10.3892/ol.2020.12069
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