M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion

Pingfang Song, Harmanjatinder S. Sekhon, Allison Lu, Juan Arredondo, David Sauer, Courtney Gravett, Gregory Mark, Sergei A. Grando, Eliot Spindel

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers.

Original languageEnglish (US)
Pages (from-to)3936-3944
Number of pages9
JournalCancer Research
Volume67
Issue number8
DOIs
StatePublished - Apr 15 2007

Fingerprint

Muscarinic Antagonists
Small Cell Lung Carcinoma
Mitogen-Activated Protein Kinases
Acetylcholine
Phosphorylation
Cholinergic Agents
Growth
Small Interfering RNA
Calcium
Cell Line
Neoplasms
Muscarinic Receptors
Nude Mice
Nervous System
Neurotransmitter Agents
Intercellular Signaling Peptides and Proteins
Hormones
Staining and Labeling
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion. / Song, Pingfang; Sekhon, Harmanjatinder S.; Lu, Allison; Arredondo, Juan; Sauer, David; Gravett, Courtney; Mark, Gregory; Grando, Sergei A.; Spindel, Eliot.

In: Cancer Research, Vol. 67, No. 8, 15.04.2007, p. 3936-3944.

Research output: Contribution to journalArticle

Song, Pingfang ; Sekhon, Harmanjatinder S. ; Lu, Allison ; Arredondo, Juan ; Sauer, David ; Gravett, Courtney ; Mark, Gregory ; Grando, Sergei A. ; Spindel, Eliot. / M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion. In: Cancer Research. 2007 ; Vol. 67, No. 8. pp. 3936-3944.
@article{94a2a426cf0a4a8abd0e902e455f5ebe,
title = "M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion",
abstract = "The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers.",
author = "Pingfang Song and Sekhon, {Harmanjatinder S.} and Allison Lu and Juan Arredondo and David Sauer and Courtney Gravett and Gregory Mark and Grando, {Sergei A.} and Eliot Spindel",
year = "2007",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-06-2484",
language = "English (US)",
volume = "67",
pages = "3936--3944",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion

AU - Song, Pingfang

AU - Sekhon, Harmanjatinder S.

AU - Lu, Allison

AU - Arredondo, Juan

AU - Sauer, David

AU - Gravett, Courtney

AU - Mark, Gregory

AU - Grando, Sergei A.

AU - Spindel, Eliot

PY - 2007/4/15

Y1 - 2007/4/15

N2 - The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers.

AB - The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers.

UR - http://www.scopus.com/inward/record.url?scp=34248597724&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248597724&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-2484

DO - 10.1158/0008-5472.CAN-06-2484

M3 - Article

C2 - 17440109

AN - SCOPUS:34248597724

VL - 67

SP - 3936

EP - 3944

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 8

ER -