Nicotinic acetylcholine receptor signaling in tumor growth and metastasis

Abstract

Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer.

Figure 1

A schematic of nAChR-mediated regulation of diverse tumorigenic processes. nAChRs are activated by tobacco smoke components like NNN, NNK, and nicotine with different affinity. Induced nAChRs activate several downstream signaling pathways involved in cell proliferation, inhibition of apoptosis, metastasis, and angiogenesis in a variety of cancer and primary cells. Agonist binding to nAChR forms complex with β-arrestin and Src and results in Raf-1 activation. Activated Raf-1 phosphorylates and inactivates Rb tumor-suppressor-function. These in turn results in E2F-1-mediated transcriptional upregulation of target genes involved in cell proliferation, angiogenesis, and inhibition of apoptosis. Downstream effect of nAChR activation is also indirectly supported by the activation of β-adrenergic receptor (β-AR) signaling. Nicotine exposure directly results in metastatic dissemination of primary tumor by inducing epithelial to mesenchymal transition (EMT) in cancer cells.