Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way

Abstract

Nicotine can stimulate the progression of non-small cell lung cancer (NSCLC) through nicotinic acetylcholine receptors (nAChRs). The persistent proliferation of cancer cells is one of the key effects of nicotinic signaling. The present study aimed to clarify the mechanism of nicotine-induced proliferation in NSCLCs at the receptor subtype level. We have previously reported that there are various subtypes of nicotinic receptors expressed in NSCLC cell lines. In the present study, we demonstrated that blocking α7nAChRs agonized by nicotine could suppress the proliferation of H1299 cells in vitro and decrease H1299 tumor xenograft growth in nude mice. During this process, the expression of vimentin was also markedly attenuated, concomitant with the decreased expression of α7nAChR. These results were ascertained by knocking down the α7nAChR gene to abolish receptor functioning. Furthermore, under the stimulation of nicotine, the MEK/ERK signaling pathway was found to be inhibited when cells were treated with an antagonist of α7nAChR or an inhibitor of MEK. Collectively the results indicate that the changes in proliferation and vimentin expression of H1299 cells in response to α7nAChR stimulation are mediated by the MEK/ERK pathway. These findings demonstrate that α7nAChR plays an important role in H1299 cell proliferation, tumor growth and expression of vimentin. Therefore, blocking α7nAChRs in NSCLC may be a potential adjuvant therapy for the targeted treatment of NSCLC.

Nicotinic-nAChR signaling mediates drug resistance in lung cancer

“…Nicotine stimulates tumor growth and ERK activation in a murine orthotopic model of lung cancer [54]. A blockade of α7nAChRs suppresses nicotine-induced lung cancer cell growth and vimentin expression through the MEK/ERK signaling pathway [63]. Consistent with these results, nicotine increased expression of nAChR and stimulated proliferation of SCC cell line [65].…”

“…α7nAChR levels in patients with SCC who are active smokers are correlated with their smoking history [31]. The function of α7nAChR-mediated lung cancer progression including in proliferation [31,[54][55][56][57][58][59][60][61][62][63][64][65], angiogenesis [66], and metastasis [39,[67][68][69], has been revealed (Fig. 2).…”

“…The nicotine-mediated α5nAChR/ AKT signaling pathway prevents cisplatin-induced cancer cell apoptosis [112]. Blockade of α7nAChRs inhibited nicotine-induced tumor growth and vimentin expression in NSCLC through the RAS-RAF-MAPK kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling pathway [63]. The nicotine and derivatives may mediate oncogenic signaling via nAChR, β-AR, and EGFR and combined with the effects of antiapoptosis in mitochondria that contribute to cancer progression (Fig.…”

α7 nicotinic acetylcholine receptors in lung cancer (Review)

“…A previous study demonstrated that exposure to nicotine resulted in α7nAChRs upregulation in human squamous cell lung cancer via the Sp1 transcription factor/GATA binding protein pathway, which accelerates tumor proliferation and progression (49). However, several signals underlying α7nAChR-induced cell proliferation included the activation of Ca2 + influx (58), Raf-1 (51,59), mitogen-activated protein kinase/ERK (27,51,59,60), c-Jun N-terminal kinase, phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt), protein kinase A (PKA) pathway (60)(61)(62), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) receptors (63), and mitogen-activated protein kinase kinase (MEK)/ERK (67). In nicotine-induced lung cancer cells, Chernyavsky et al (63) revealed that the activation of cell membrane α7nAChR resulted in the association with EGF receptors, whereas activated mitochondrial α7nAChR physically associated with the intramitochondrial protein kinases PI3K and Src.…”

“…In nicotine-induced lung cancer cells, Chernyavsky et al (63) revealed that the activation of cell membrane α7nAChR resulted in the association with EGF receptors, whereas activated mitochondrial α7nAChR physically associated with the intramitochondrial protein kinases PI3K and Src. Zhang et al (67) demonstrated that the blockade of α7nAChR specifically inhibited nicotine-stimulated tumor growth in NSCLC through the MEK/ERK signaling pathway. It has also been reported that α7nAChRs mediate the pro-proliferative effects of nicotine through activating Akt and ERK pathways, and blocking α7nAChRs eliminates nicotine-induced proliferation and signaling in A549 cells (68).…”