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Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors

Most patients treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) eventually develop acquired resistance. Loss of expression of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) has been suggested as a possible mechanism of resistance to EGFR-TKIs in the A431 and HN11 cell lines. Her...

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Autores principales: Choi, Yun Jung, Park, Gun Min, Rho, Jin Kyung, Kim, Sun Ye, So, Gwang Sup, Kim, Hyeong Ryul, Choi, Chang-Min, Lee, Jae Cheol
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855319/
https://www.ncbi.nlm.nih.gov/pubmed/24339922
http://dx.doi.org/10.1371/journal.pone.0081393
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author Choi, Yun Jung
Park, Gun Min
Rho, Jin Kyung
Kim, Sun Ye
So, Gwang Sup
Kim, Hyeong Ryul
Choi, Chang-Min
Lee, Jae Cheol
author_facet Choi, Yun Jung
Park, Gun Min
Rho, Jin Kyung
Kim, Sun Ye
So, Gwang Sup
Kim, Hyeong Ryul
Choi, Chang-Min
Lee, Jae Cheol
author_sort Choi, Yun Jung
collection PubMed
description Most patients treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) eventually develop acquired resistance. Loss of expression of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) has been suggested as a possible mechanism of resistance to EGFR-TKIs in the A431 and HN11 cell lines. Here, we investigated IGFBP-3 expression in two EGFR mutant lung cancer cell lines with resistance to EGFR-TKIs and examined the value of serum IGFBP-3 level as a marker of resistance. The effect of the induction or suppression of IGFBP-3 expression on resistance was also evaluated. HCC827 sublines with resistance to gefitinib (HCC827/GR) and erlotinib (HCC827/ER) were established. Loss of IGFBP-3 expression was detected by Western blotting in both cell lines without changes in transcriptional activity, and ELISA showed significantly lower amounts of secreted IGFBP-3 in the culture media of the mutant cell lines than in that of the parental line. Despite the loss of IGFBP-3 expression, IGFR signalling activity remained unchanged. Forced expression of IGFBP-3 by adenovirus-mediated transfection or recombinant IGFBP-3 slightly increased the growth-inhibitory and apoptotic effects of EGFR-TKIs, whereas suppression of IGFBP-3 did not affect sensitivity to EGFR-TKI. Serum IGFBP-3 levels measured by ELISA before and after the development of EGFR-TKI resistance in 20 patients showed no significant changes (1815.3±94.6 ng/mL before treatment vs. 1778.9±87.8 ng/mL after EGFR-TKI resistance). In summary, although IGFBP-3 downregulation is associated with the acquisition of resistance to EGFR-TKIs regardless of the mechanism, its effect on resistance was not significant, indicating that IGFBP-3 may not play an important role in resistance to EGFR-TKIs and serum IGFBP-3 level is not a reliable indicator of resistance.
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spelling pubmed-38553192013-12-11 Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors Choi, Yun Jung Park, Gun Min Rho, Jin Kyung Kim, Sun Ye So, Gwang Sup Kim, Hyeong Ryul Choi, Chang-Min Lee, Jae Cheol PLoS One Research Article Most patients treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) eventually develop acquired resistance. Loss of expression of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) has been suggested as a possible mechanism of resistance to EGFR-TKIs in the A431 and HN11 cell lines. Here, we investigated IGFBP-3 expression in two EGFR mutant lung cancer cell lines with resistance to EGFR-TKIs and examined the value of serum IGFBP-3 level as a marker of resistance. The effect of the induction or suppression of IGFBP-3 expression on resistance was also evaluated. HCC827 sublines with resistance to gefitinib (HCC827/GR) and erlotinib (HCC827/ER) were established. Loss of IGFBP-3 expression was detected by Western blotting in both cell lines without changes in transcriptional activity, and ELISA showed significantly lower amounts of secreted IGFBP-3 in the culture media of the mutant cell lines than in that of the parental line. Despite the loss of IGFBP-3 expression, IGFR signalling activity remained unchanged. Forced expression of IGFBP-3 by adenovirus-mediated transfection or recombinant IGFBP-3 slightly increased the growth-inhibitory and apoptotic effects of EGFR-TKIs, whereas suppression of IGFBP-3 did not affect sensitivity to EGFR-TKI. Serum IGFBP-3 levels measured by ELISA before and after the development of EGFR-TKI resistance in 20 patients showed no significant changes (1815.3±94.6 ng/mL before treatment vs. 1778.9±87.8 ng/mL after EGFR-TKI resistance). In summary, although IGFBP-3 downregulation is associated with the acquisition of resistance to EGFR-TKIs regardless of the mechanism, its effect on resistance was not significant, indicating that IGFBP-3 may not play an important role in resistance to EGFR-TKIs and serum IGFBP-3 level is not a reliable indicator of resistance. Public Library of Science 2013-12-05 /pmc/articles/PMC3855319/ /pubmed/24339922 http://dx.doi.org/10.1371/journal.pone.0081393 Text en © 2013 Choi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Choi, Yun Jung
Park, Gun Min
Rho, Jin Kyung
Kim, Sun Ye
So, Gwang Sup
Kim, Hyeong Ryul
Choi, Chang-Min
Lee, Jae Cheol
Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors
title Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors
title_full Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors
title_fullStr Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors
title_full_unstemmed Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors
title_short Role of IGF-Binding Protein 3 in the Resistance of EGFR Mutant Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitors
title_sort role of igf-binding protein 3 in the resistance of egfr mutant lung cancer cells to egfr-tyrosine kinase inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855319/
https://www.ncbi.nlm.nih.gov/pubmed/24339922
http://dx.doi.org/10.1371/journal.pone.0081393
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