Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker
It is well-recognized that cigarette smoking is a primary risk factor in the development of non-small cell lung cancer (NSCLC), known to account for ~80% of all lung cancers with nicotine recognized as the major addictive component. In investigating the effect of nicotine, brain-derived neurotrophic...
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MDPI AG
2022-10-01
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author | Ravel Ray Hind Al Khashali Ben Haddad Jadziah Wareham Kai-Ling Coleman Danyah Alomari Robert Ranzenberger Jeffrey Guthrie Deborah Heyl Hedeel Guy Evans |
author_facet | Ravel Ray Hind Al Khashali Ben Haddad Jadziah Wareham Kai-Ling Coleman Danyah Alomari Robert Ranzenberger Jeffrey Guthrie Deborah Heyl Hedeel Guy Evans |
author_sort | Ravel Ray |
collection | DOAJ |
description | It is well-recognized that cigarette smoking is a primary risk factor in the development of non-small cell lung cancer (NSCLC), known to account for ~80% of all lung cancers with nicotine recognized as the major addictive component. In investigating the effect of nicotine, brain-derived neurotrophic factor (BDNF), and the β-adrenergic receptor blocker, propranolol, on sensitivity of NSCLC cell lines, A549 and H1299, to cisplatin, we found increased cell viability, and enhanced cisplatin resistance with nicotine and/or BDNF treatment while opposite effects were found upon treatment with propranolol. Cell treatment with epinephrine or nicotine led to EGFR and IGF-1R activation, effects opposite to those found with propranolol. Blocking EGFR and IGF-1R activation increased cell sensitivity to cisplatin in both cell lines. PI3K and AKT activities were upregulated by nicotine or BDNF and downregulated by cell treatment with inhibitors against EGFR and IGF-1R and by propranolol. Apoptosis and cell sensitivity to cisplatin increased upon co-treatment of cells with cisplatin and inhibitors against PI3K or AKT. Our findings shed light on an interplay between nicotine, BDNF, and β-Adrenergic receptor signaling in regulating survival of lung cancer cells and chemoresistance which can likely expand therapeutic opportunities that target this regulatory network in the future. |
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language | English |
last_indexed | 2024-03-09T19:01:59Z |
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spelling | doaj.art-d3ea212379724065998a99f88db970702023-11-24T04:57:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211282910.3390/ijms232112829Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor BlockerRavel Ray0Hind Al Khashali1Ben Haddad2Jadziah Wareham3Kai-Ling Coleman4Danyah Alomari5Robert Ranzenberger6Jeffrey Guthrie7Deborah Heyl8Hedeel Guy Evans9Chemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAChemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USAIt is well-recognized that cigarette smoking is a primary risk factor in the development of non-small cell lung cancer (NSCLC), known to account for ~80% of all lung cancers with nicotine recognized as the major addictive component. In investigating the effect of nicotine, brain-derived neurotrophic factor (BDNF), and the β-adrenergic receptor blocker, propranolol, on sensitivity of NSCLC cell lines, A549 and H1299, to cisplatin, we found increased cell viability, and enhanced cisplatin resistance with nicotine and/or BDNF treatment while opposite effects were found upon treatment with propranolol. Cell treatment with epinephrine or nicotine led to EGFR and IGF-1R activation, effects opposite to those found with propranolol. Blocking EGFR and IGF-1R activation increased cell sensitivity to cisplatin in both cell lines. PI3K and AKT activities were upregulated by nicotine or BDNF and downregulated by cell treatment with inhibitors against EGFR and IGF-1R and by propranolol. Apoptosis and cell sensitivity to cisplatin increased upon co-treatment of cells with cisplatin and inhibitors against PI3K or AKT. Our findings shed light on an interplay between nicotine, BDNF, and β-Adrenergic receptor signaling in regulating survival of lung cancer cells and chemoresistance which can likely expand therapeutic opportunities that target this regulatory network in the future.https://www.mdpi.com/1422-0067/23/21/12829β-adrenergic receptorsbrain-derived neurotrophic factorlung cancercisplatinnicotineEGFR |
spellingShingle | Ravel Ray Hind Al Khashali Ben Haddad Jadziah Wareham Kai-Ling Coleman Danyah Alomari Robert Ranzenberger Jeffrey Guthrie Deborah Heyl Hedeel Guy Evans Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker International Journal of Molecular Sciences β-adrenergic receptors brain-derived neurotrophic factor lung cancer cisplatin nicotine EGFR |
title | Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker |
title_full | Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker |
title_fullStr | Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker |
title_full_unstemmed | Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker |
title_short | Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker |
title_sort | regulation of cisplatin resistance in lung cancer cells by nicotine bdnf and a β adrenergic receptor blocker |
topic | β-adrenergic receptors brain-derived neurotrophic factor lung cancer cisplatin nicotine EGFR |
url | https://www.mdpi.com/1422-0067/23/21/12829 |
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