Figure 4.

Schematic of mediation of tumor-promoting actions by nicotine/nAChR. Nicotine interacts with nAChR and stimulates activation and crosstalk with β-AR and EGFR downstream, signaling to promote cancer progression. Activation of nAChRs and β-AR mediates EGF secretion to further transactivate EGFRs. In cancer cells, the signaling pathways downstream of nAChRs promote drug resistance and antiapoptosis by activating the transcription factors including STAT, NF-κB, Jun/Fos, and E2F through JAK, PI3K/AKT, RAS, RAF, and the MAPK signaling cascade. Mitochondrial nAChRs trigger phosphatidyl-inositol-3-kinase (PI3K) and AKT signaling pathways that prevent mPTP opening and cytochrome c release. Nicotine-induced antiapoptosis and drug resistance may include several mechanisms involved in overexpression of sirtuin proteins, phosphorylation of BAD, and blockade of BAX translocation, leading to tumor cell development. SIRT3 and SIRT5 are mitochondrial proteins. SIRT6 and SIRT7 are localized in the nucleus. SIRT1-mediated deacetylation of FOXO3a can induce expression of antioxidant enzymes including MnSOD and catalase that increase cell survival during cellular oxidative stress. Consequently, nicotine/nAChR mediates antiapoptotic pathways and concurrently crosstalks with β-AR or EGFR signaling activation may lead to cancer progression. N: nicotine; Ac: acetylation; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.