Abstract
Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis, but the precise mechanisms involved remain largely unknown. Here, we investigated the mechanism of action of nicotine in human nasopharyngeal carcinoma (NPC) cells. Nicotine significantly promoted cell proliferation in a dose and time-dependent manner in human NPC cells. The mechanism studies showed that the observed stimulation of proliferation was accompanied by the nicotine-mediated simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling. Treatment of NPC cells with nicotine markedly upregulated the expression of α7AChR and HIF-1α proteins. Transfection with a α7AChR or HIF-1α-specific siRNA or a α7AChR-selective inhibitor significantly attenuated the nicotine-mediated promotion of NPC cell proliferation. Nicotine also promoted the phosphorylation of ERK1/2 but not JNK and p38 proteins, thereby induced the activation of ERK/MAPK signaling pathway. Pretreatment with an ERK-selective inhibitor effectively reduced the nicotine-induced proliferation of NPC cells. Moreover, nicotine upregulated the expression of VEGF but suppressed the expression of PEDF at mRNA and protein levels, leading to a significant increase of the ratio of VEGF/PEDF in NPC cells. Pretreatment with a α7AChR or ERK-selective inhibitor or transfection with a HIF-1α-specific siRNA in NPC cells significantly inhibited the nicotine-induced HIF-1α expression and VEGF/PEDF ratio. These results therefore indicate that nicotine promotes proliferation of human NPC cells in vitro through simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling and suggest that the related molecules such as HIF-1α might be the potential therapeutic targets for tobacco-associated diseases such as nasopharyngeal carcinomas.
Highlights
Nasopharyngeal carcinoma (NPC) has the highest occurrence in Southeast Asia and is one of the leading causes for cancer mortality in Cantonese region of Southern China [1,2]
To determine whether nicotine may regulate the proliferation of nasopharyngeal carcinoma (NPC) cells, we examined the effect of nicotine on cell viability in various kinds of human NPC cell lines, including nasopharyngeal high differentiated squamous epithelium carcinoma cell line CNE1, nasopharyngeal low differentiated squamous epithelium carcinomas cell line CNE2 as well as its clones S18 and S26, by a MTT analysis
We found that nicotine promoted the expression of HIF-1a protein, leading to an activation of downstream hypoxia-responsive genes associated with tumor cell proliferation
Summary
Nasopharyngeal carcinoma (NPC) has the highest occurrence in Southeast Asia and is one of the leading causes for cancer mortality in Cantonese region of Southern China [1,2]. The effect of nicotine on tumorigenesis and angiogenesis of human NPC and the mechanism of action of nicotine involved remain largely unknown. Several lines of evidence suggest that nicotine exerts its cellular functions through nicotinic acetyl-choline receptors (nAChRs), which are widespread in neurons, neuromuscular junctions and many tumor cells [10,11]. Previous studies have shown that nicotine functions through its interaction with a7AChR [12,13]. A7AChR is a kind of integral membrane protein, which is highly expressed in a portion of tumors and closely associated with cancer cells growth, migration, angiogenesis, and apoptosis [14]. No information has been available about whether nicotine affects proliferation of human NPC cells through regulation of the a7AChR
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
