Nicotine‐Mediated Ca²⁺‐Influx Induces IL‐8 Secretion in Oral Squamous Cell Carcinoma Cell

Abstract

Cigarette smoking is one of the most important risk factors for the development of various diseases. Nicotine is the most extensively investigated component of cigarette smoke, and a comprehensive analysis of the genes induced by nicotine stimulation revealed that interleukin-8 (IL-8) was induced in oral squamous cell carcinoma cell (OSCC). Based on this background, the signaling mechanisms of nicotine-mediated IL-8 induction in OSCC was investigated. Augmented IL-8 secretion by Ca9-22 cells was blocked by the NF-κB inhibitor L-1-4'-tosylamino-phenylethyl-chloromethyl ketone (TPCK) and the nicotinic acetylcholine receptor (nAChR)-specific inhibitor α-bungarotoxin (αBtx). The downstream signaling pathway was further examined by pre-incubating the cells with inhibitors against mitogen-activated protein kinase (MEK), protein kinase C (PKC), and Ca(2+)/calmodulin-dependent kinase II (CaMK II). Only the CaMK II inhibitor was found to exert an inhibitory effect on nicotine-mediated IL-8 secretion. Pre-treatment of the Ca9-22 cells with the Ca(2+) chelator BAPTA-AM drastically inhibited IL-8 secretion. Although nicotine stimulation induced the phosphorylation of the NF-κB p65 subunit, pre-treatment with BAPTA-AM was found to inhibit this activity significantly. CaMK II-dependent p65 phosphorylation was confirmed by pre-incubation of the cells with CaMK II inhibitor. The results from this study indicate that the binding of nicotine to nAChR induces Ca(2+) influx, which results in the activation and phosphorylation of CaMK II and NF-κB p65, respectively. Nicotine-mediated IL-8 induction should be a trigger for the initiation of various diseases.

Genomic and Transcriptomic Characterization Links Cell Lines with Aggressive Head and Neck Cancers

“…Most HPV(+) lines exhibited higher expression of 3q27 gene DVL3 implicated in Wnt-b-catenin pathway signaling. Other potentially interesting 3q26-qter candidates expressed across the lines include calmodulin kinase II CAMK2N2 , implicated in nicotine-induced activation of transcription factor NF-kB and inflammatory and angiogenesis factor IL-8 ( Tsunoda et al, 2016 ), and ephrin EPHB3 , reported to promote migration in lung cancer ( Efazat et al, 2016 ). In contrast, HPV(−) lines and HPV(+) pair UPCI:SCC090/152 derived from a patient with primary and recurrent tumors who died within 22 months more often showed broader 3q arm gains with increased expression of MAP3K13 (LZK), a kinase recently reported to stabilize mutant TP53 in HNSCC ( Edwards et al, 2017 ); ACTL6A , which cooperates with 3q gene TP63 and 11q22 Hippo pathway gene YAP1 , linked to growth and poor patient survival in HNSCC ( Saladi et al, 2017 ); PI3K-mTOR-eIF growth pathway ( Iglesias-Bartolome et al, 2013 ) genes PIK3CA , EIF4A2 , EIF2A , EIF2B5 , and EIF5A2 ; and ZNF639 (ZASC), a zinc finger transcription factor associated with recurrent oral squamous cell carcinoma (SCC) ( Chiang et al, 2011 ).…”

Nicotine Induces IL-8 Secretion from Pancreatic Cancer Stroma and Worsens Cancer-Induced Cachexia

“…Importantly, a number of other studies have demonstrated the effects of nicotine on IL-8 secretion by cancer cells. Oral epidermoid carcinoma cells and oral squamous cell carcinoma cells are induced to secrete IL-8 by nicotine [21,22]. Similarly, nicotine has been shown to induce IL-8 production by periodontal ligament cells upon binding the α7 nAChR [23].…”

“…IL-8 levels are also associated with cachexia in prostate and gastroesophageal cancers [19,20]. Certain [21,22]. Similarly, nicotine has been shown to induce IL-8 production by periodontal ligament cells upon binding the α7 nAChR [23].…”

Role of tumour-associated macrophages in oral squamous cells carcinoma progression: an update on current knowledge

“…It is probable that Porphyromonas gingivalis contributes to OSCC progression, increasing IL-8 levels in the microenvironment and upregulating MMPs [53]. Nicotine also increases IL-8 release in OSCC, binding to the nicotine acetylcholine receptor (nAChR) and inducing calcium influx, that phosphorylates Ca(2+)/calmodulin-dependent kinase II (CaMK II) and NF-κB [54]. …”