Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells

Carlisle, Diane L.; Liu, Xuwan; Hopkins, Toni M.; Swick, Michelle C.; Dhir, Rajiv; Siegfried, Jill M.

doi:10.1016/j.pupt.2006.07.001

Cited by 92 publications

(82 citation statements)

References 51 publications

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“…It has been reported that cholinergic stimulation leads to cell proliferation through MAPK and Akt pathways. 27,33 In this study, in parallel with stimulation of A549 and PC9 cell proliferation by either carbachol or pilocarpine, phosphorylation of MAPK and Akt was increased ( Fig. S2 and S3).…”

Section: Discussionsupporting

confidence: 56%

“…4D and 4F) as did methoctramine. Of note, studies have shown that interaction of nicotine with nicotinic receptors also leads to increased Akt and MAPK phosphorylation 33 ; thus, ACh secreted by lung tumors may also stimulate Akt and MAPK phosphorylation through interaction with nAChR. Therefore, in smokers with lung cancer, cholinergicmediated proliferative pathways will be stimulated by exogenous nicotine and endogenous ACh.…”

Section: Discussionmentioning

confidence: 99%

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Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

Zhao

Zhang

et al. 2015

Cancer Biology & Therapy

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These authors contributed equally to this work.Keywords: autoparacrine, AKT, epithelial-mesenchymal transition, MAPK ERK, M2 muscarinic receptor, non-neuronal acetylcholine, non-small cell lung cancerAbbreviations: NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; ACh, acetylcholine; AChR, acetylcholine receptor; mAChR, muscarinic receptor; nAChR, nicotinic receptor; M2R, M2 mAChR; EMT, epithelial-mesenchymal transition; ChAT, choline acetyltransferase; MAPK, mitogen-activated protein kinase; shRNA, short hairpin RNA.Lung cancers express non-neuronal, cholinergic autoparacrine loop, which facilitates tumor growth. Interruption of M3 muscarinic cholinergic signaling has been reported to inhibit small cell lung cancer (SCLC) growth. The purpose of this study is to investigate if blocking autoparacrine muscarinic cholinergic signaling could inhibit non-small cell lung cancer (NSCLC) growth and possible underlying mechanisms. Our results showed that PC9 and A549 cells expressed all 5 subtypes of muscarinic receptor (mAChR) and blocking M2 mAChR (M2R) signaling using selective antagonist methoctramine or short hairpin RNA (shRNA) inhibited tumor cell proliferation in vitro and in vivo. Consistent with AChR agonists stimulating p44/42 MAPK (Erk1/2) and Akt phosphorylation, blocking M2R signaling decreased MAPK and Akt phosphorylation, indicating that non-neuronal ACh functions as an autoparacrine growth factor signaling in part through activation of M2R and downstream MAPK and Akt pathways. Importantly, further studies revealed that blocking M2R signaling also reversed epithelial-mesenchymal transition (EMT) in vitro and in vivo, indicating that nonneuronal ACh promotes EMT partially through activation of M2R. These findings demonstrate that M2R plays a role in the growth and progression of NSCLC and suggest M2R antagonists may be an efficacious adjuvant therapy for NSCLC.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

Zhao

Zhang

et al. 2015

Cancer Biology & Therapy

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“…Nicotine and its derivatives play important roles in the stimulation of NSCLC growth (Catassi et al, 2008;. In this regard, nicotinic acetylcholine receptors (nAChRs), beta-ARs (Schuller et al, 1999) and the activation of the betaadrenergic signaling cascade (Schuller et al, 1999;Laag et al, 2006) and the Akt pathway (Carlisle et al, 2007) are important, as shown in many animal studies (Schuller and Orloff, 1998;Schuller et al, 2000;West et al, 2004;Arredonda et al, 2006;Schuller, 2008;2009). Nicotine causes a deficiency in GABA, an antagonist of betaadrenergic signalling .…”

Section: Discussionmentioning

confidence: 99%

Does Beta-blocker Therapy Improve the Survival of Patients with Metastatic Non-small Cell Lung Cancer?

Aydıner

Çiftçi²,

Karabulut³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…Many growth factors and their downstream effectors are aberrantly activated or overexpressed, contributing to growth deregulation in cancer. It has been reported that the addition of nicotine increases EGF receptor (EGFR) expression in lung, breast, gastric, and colon cells (54)(55)(56)(57). After recruiting downstream effectors, growth-related receptors often exert their functions by organizing their downstream effectors to initiate signaling cascades in such pathways as PKC, PI3K/Akt, and MAPK.…”

Section: Smoking-induced Cancer Formationmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor-Based Blockade: Applications of Molecular Targets for Cancer Therapy

Lee

2011

Clinical Cancer Research

103

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The nicotinic acetylcholine receptor (nAChR) was first characterized in 1970 as a membrane receptor of a neurotransmitter and an ion channel. nAChRs have been shown to be involved in smoking-induced cancer formation in multiple types of human cancer cells. In vitro and in vivo animal studies have shown that homopentameric nAChR inhibitors, such as methyllycaconitine and a-Bgtx, can attenuate nicotine-induced proliferative, angiogenic, and metastatic effects in lung, colon, and bladder cancer cells. Recent publications have shown that a9-nAChR is important for breast cancer formation, and in many in vivo studies, a9-nAChR-specific antagonists (e.g., a-ImI, a-ImI, Vc1.1, RgIA, and It14a) produced an analgesic effect. Vc1.1 functions in a variety of animal pain models and currently has entered phase II clinical trials. For cancer therapy, natural compounds such as garcinol and EGCG have been found to block nicotine-and estrogeninduced breast cancer cell proliferation through inhibition of the a9-nAChR signaling pathway. A detailed investigation of the carcinogenic effects of nAChRs and their specific antagonists would enhance our understanding of their value as targets for clinical translation.

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Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells

Cited by 92 publications

References 51 publications

Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

Does Beta-blocker Therapy Improve the Survival of Patients with Metastatic Non-small Cell Lung Cancer?

Nicotinic Acetylcholine Receptor-Based Blockade: Applications of Molecular Targets for Cancer Therapy

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