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. 2012 May 23;33(9):1617–1628. doi: 10.1093/carcin/bgs186

Fig. 1.

Fig. 1.

Interconnected signaling cascades for CS-mediated pancreatic injury. CS produces various components, including nicotine, nitrosamines (NNK), and PAH that cause the pancreatic injury. (A) Both nicotine and NNK are selective agonists for α7nAChR, which upon binding causes the cell depolarization and lead to an enhanced influx of cations including calcium ions through voltage-dependent channels. Calcium ions mediate the nicotine entry into the pancreatic cells inducing altered exocrine pancreatic secretions associated with pancreatic injury. Enhanced calcium influx triggers the release and synthesis of excitatory neurotransmitters (adrenalin and noradrenalin) that activates the adenylyl cyclase downstream of Gαs-coupled receptors. GABA normally balances these effects by inhibiting adenylyl cyclase downstream of the Gαi-coupled GABA receptor through a α4β2nAChR-dependent mechanism. Both nicotine and NNK desensitizes the α4β2nAChR, hence inhibiting the release and synthesis of GABA and virtually shutting down all inhibitory GABA signaling. (B) NNK and nicotine leads to the stimulation of the cell proliferation, migration, and angiogenesis either by the direct activation of the β-adrenoreceptor-mediated signaling via cAMP/PKA/p-CREB or indirectly by regulating the release and synthesis of EGF, VEGF, or arachidonic acid and PKA-mediated transactivation of EGFR. This leads to the nicotine/NNK-mediated indirect induction of the Ras-Raf-MEK ERK pathway. (C) MAPK pathway and nicotine/α7nAChR-mediated JAK2/STAT3 pathway further stimulates the upregulation of the genes such as MYC, CYP, KRAS, FOS, and JUN in the nucleus, inhibiting the apoptosis of the cells and causing cells to proliferate and grow. (D) Nicotine elicits a prometastatic response in pancreatic cells by stimulation of osteopontin production through α7 nAChR-dependent mechanism. Nicotine can also induce through EGFR/AKT/NFκB-mediated pathways, changes in gene expression consistent with epithelial to mesenchymal transition (EMT). PAH also contributes to the cell metastasis by inducing the release of arachidonic acid and inhibiting the gap junctional intercellular communication. (E) The carcinogens NNK and PAH can be metabolically activated to intermediates that react with DNA, forming DNA adducts resulting in the mutation of crucial genes such as KRAS gene. If the DNA adducts are repaired by cellular repair enzymes, DNA is returned to its normal undamaged state. Nicotine is able to enhance the production of ROS, which plays an important role in inhibiting the DNA repair mechanism of the cell. Also, increase in the ROS has been directly linked to the lipid peroxidation leading to the pancreatic injury. Cells with damaged or mutated DNA can be removed by apoptosis, which is inhibited by nicotine as it regulates EGFR leading to activation of the serine threonine kinase, AKT, and other factors such as NFκB and Bcl2, causing decreased apoptosis. The red arrows merge the various pathways defining their specific role in modulating the functional properties of PC cells such as proliferation, angiogenesis, migration, EMT, and reduced apoptosis. AA, aromatic amines; AKT, cAMP, Cyclic adenosine monophosphate; COX-2, cyclooxygenase-2; CREB, “http://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate” \o “Cyclic adenosine monophosphate” cAMP response element-binding; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; GABA, γ-aminobutyric acid; GPCRs, G‑protein coupled receptors; JAK2, Janus kinase 2; MAPK, mitogen activated protein kinase; nAChR, nicotinic acetylcholine receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;OPN, osteopontin; PAH’s, polycyclic aromatic hydrocarbons; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor- β; VEGF, Vascular endothelial growth factor.