Decoding the role of nicotinic receptors in prostate and colon cancer
Nicotinic acetylcholine receptors(opens in new window) (nAChRs) are transmembrane ion channels that become activated by the neurotransmitter acetylcholine or the drug nicotine. They consist of five subunits which are encoded by 16 different genes and thus exhibit diverse properties and functions. Although nAChRs are widely expressed throughout the peripheral and central nervous system, they are also found throughout the entire body. In addition to their well-described ionotropic properties, these receptors also activate several intracellular signalling pathways in neurons and other cell types. It is well-established that tobacco smoking correlates with several cancer types, as nicotine and tobacco-derived nitrosamines activate nAChRs, contributing to cancer progression and chemotherapy resistance. In lung cancer, nicotine exposure through interaction with nAChRs is known to increase cell proliferation, epithelial to mesenchymal transition and cell invasion. However, the specific contributions of nAChRs to the pathophysiology of prostate and colon cancers remain unexplored.
nAChR expression in cancer
Undertaken with the support of the Marie Skłodowska-Curie Actions(opens in new window) (MSCA) programme, the nAChRs-CRC-PCa-IF-RI project aimed to identify and characterise the specific nAChRs involved in prostate and colon cancers. “We wanted to understand the roles of these receptors in cellular processes such as migration, proliferation and invasion,” explains MSCA research fellow Maria Maldifassi. Researchers studied nAChR levels across breast, colon and prostate cancer cells and observed distinct expression patterns. In particular, the expression of the alpha-5 nicotinic subunit(opens in new window) was found to be crucial for nicotine-induced proliferation and migration. Downregulation of alpha-5 impaired the migration of cancer cells by reducing the expression of epithelial-mesenchymal transition (EMT) markers and immune regulatory proteins, typically promoted by nicotine. Another critical discovery was the impact of the gene variant of the alpha-5 subunit (polymorphism D398N), which is linked to nicotine dependence in lung cancer. This polymorphism caused a basal increase in proliferation and migration in prostate cancer cells. Collectively, these results suggest that nicotine-induced cancer cell proliferation and migration are mediated via alpha-5, making it a potential therapeutic target.
3D cancer models
The projects successfully used 3D cultures(opens in new window) to assess the effects of nicotine on cancer cell viability and marker expression. The findings indicated that nicotine activation of nAChRs could modify viability and upregulate cancer markers in lung but not in prostate cancer-derived spheres. Compared to conventional 2D cultures, these 3D cancer models resemble more the physiological environment for the study of immune cell invasion and migration in solid tumours.
Future directions
“Overall, the project advanced our understanding of the tumour-promoting effects of nicotine beyond lung cancer. It showed that nicotine consumption is also associated with prostate cancer, colorectal cancer and breast cancer, highlighting the potential of the alpha-5 subunit to serve as a therapeutic target,” highlights Maldifassi. Looking ahead, the research team plans to establish 3D cancer models, such as zebrafish and patient-derived xenografts, and employ pharmacological approaches to further investigate the role of the alpha-5 subunit in the pro-oncogenic mechanisms of cancer. Additionally, the development of 3D cancer models will be instrumental in exploring the roles of other ion channels in cancer progression.
