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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Main Authors: Ravel Ray, Hind Al Khashali, Ben Haddad, Jadziah Wareham, Kai-Ling Coleman, Danyah Alomari, Robert Ranzenberger, Jeffrey Guthrie, Deborah Heyl, Hedeel Guy Evans
Format: Article
Language:English
Published: MDPI AG 2022-10-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/23/21/12829
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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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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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