Regulation and Function of Neuronal Nicotinic Acetylcholine Receptors in Lung Cancer: A Dissertation

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide. The main risk factor associated with lung cancer is cigarette smoking. Research through the years suggests that nicotine in cigarettes promotes lung cancer by activating signaling pathways that lead to cell proliferation, cell survival, angiogenesis, and metastasis. Nicotine’s cellular actions are mediated by its cognate receptors, nicotinic acetylcholine receptors (nAChRs). Here, I describe the expression levels of all known human nAChR subunit genes in both normal and lung cancer cells. Of note, the genes encoding the α5, α3, and β4 subunits (CHRNA5/A3/B4) are over-expressed in small cell lung carcinoma (SCLC), the most aggressive form of lung cancer. This over-expression is regulated by ASCL1, a transcription factor important in normal lung development and lung carcinogenesis. The CHRNA5/A3/B4 locus has recently been the focus of a series of genetic studies showing that polymorphisms in this region confer risk for both nicotine dependence and lung cancer. I show that CHRNA5/A3/B4 depletion results in decreased SCLC cell viability. Furthermore, while nicotine promotes SCLC cell viability and tumor growth, blockade of α3β4 nAChRs inhibits SCLC cell viability. These results suggest that increased expression and function of nAChRs, specifically the α3β4α5 subtype, potentiate the effects of nicotine in SCLC. This dual hit from the carcinogens in tobacco and the cancer-promoting effects of nicotine, may provide a possible mechanism for the increased aggressiveness of SCLC. In addition, nAChRs can be activated by the endogenous ligand,