Molecular Mechanisms of Tobacco-derived Nitrosamines in Oral Squamous Cell Carcinoma (OSCC)
Kassym-Jomart Tokayev
L.N. Gumilyov Eurasian National University, city of Nur-Sultan
Keywords: Tobacco-specific nitrosamines (TSNAs), Oral squamous cell carcinoma (OSCC), DNA adducts, Epigenetic changes, PI3K/Akt/mTOR pathway
Abstract
Background: Oral squamous cell carcinoma (OSCC) is a prevalent malignancy of the head and neck, predominantly driven by tobacco consumption. The risk is exacerbated when combined with alcohol. Among the various carcinogens in tobacco, tobacco-specific nitrosamines (TSNAs), such as N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), stand out as the most potent in relation to OSCC.
Methods: This study explores the molecular pathways through which TSNAs contribute to OSCC.
Findings: Metabolically activated TSNAs can form DNA adducts that may lead to mutations, especially when affecting genes that control cell growth or apoptosis. These mutations can activate oncogenes or inactivate tumor suppressor genes, facilitating cellular transformation and the progression of tumors. Concurrently, tobacco products initiate chronic inflammation, releasing reactive species that damage DNA. This inflammation also promotes cell proliferation and angiogenesis, bolstering tumor growth. Furthermore, TSNAs can induce epigenetic changes, such as DNA methylation and histone modifications, which can alter gene activity and contribute to carcinogenesis. Additionally, TSNAs have been found to activate the PI3K/Akt/mTOR pathway, pivotal for regulating cell growth and preventing apoptosis, thereby promoting an environment conducive for tumor survival and growth.
Implications: Understanding these molecular pathways may lead to the development of early detection biomarkers. This knowledge also presents opportunities for creating targeted therapies specific to the pathways involved in OSCC progression. However, the primary preventive strategy remains abstention from tobacco products. Increased awareness regarding the molecular repercussions of tobacco consumption can serve as a potent deterrent.
Conclusion: The presence of TSNAs in tobacco plays a significant role in the onset and progression of OSCC through various molecular mechanisms. This in-depth molecular understanding is invaluable for devising both preventive strategies against tobacco use and the development of therapeutic treatments for OSCC.
