Fig 8. Schematic Depicting Signaling Cascades Initiated by Nicotine-Mediated Activation of the α7 nAChR and Inhibitors Used to Target these Pathways in this Study.

Upon nicotine binding to α7 nAChR, oligomeric complexes form including the receptor, β-arrestin-1 scaffolding protein, and Src kinase. This activates Src, resulting in activation of Raf-1 kinase which acts along with activated CDK/cyclins to hyperphosphorylate the Rb tumor suppressor, resulting in its dissociation from E2F transcription factors, allowing them to activate their target genes including a number of genes involved in multiple aspects of tumor progression. The PI3K-AKT and MAPK signaling pathways are also known to be activated by nicotine-mediated α7 nAChR activation subsequent to Src phosphorylation; and activation of MEK-ERK is known to result in activation of CDK/cyclin complexes. AKT1 activation downstream of PI3KC in response to nicotine has additionally been shown to result in activation of NFκB transcription factors. Further, Src activates STAT proteins up nicotine-mediated activation of α7 nAChR. Inhibitors used in this study are depicted in black and white boxes, and their targets are indicated accordingly.