Nicotine-derived nitrosamines promote renal cell carcinoma cell migration via binding to nicotinic acetylcholine receptors

Abstract

Several risk factors such as smoking, obesity, diabetes, and hypertension are related to the incidence of kidney cancer. Renal cell carcinoma (RCC) originates from the renal tubular epithelium and is the major form of kidney cancer. Notably, the relative risk of RCC in smokers compared to non-smokers is 1.38 while revealing a dose-dependent risk reduction in smoking cessation. Carcinogenic substances in tobacco, specifically nicotine-derived nitrosamines like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), were known to induce the formation of DNA adducts, mutating genes that potentially initiate cancers. In addition to carcinogenesis, nicotine-derived nitrosamines may also contribute to modify the malignant features, which accelerates the cancer progression. This study was aimed to evaluate the effects of NNK in the modulation RCC cell proliferation and motility, besides, the possible underlying mechanisms were also studied. Our findings showed differential expression of nicotinic acetylcholine receptor (nAChR) mRNA subunits between normal human renal tubular cell (HK-2) and RCC cells (Achn), suggesting that RCC cells may have the ability in respond to the stimuli of NNK. While NNK didn't significantly show an influence in RCC cell viability, it enhanced cell motility and migration ability. Utilizing specific inhibitors, it was inferred that NNK stimulates RCC cell migration via nAChR activation and subsequent calcium channel opening. Our research underscores the necessity of smoking cessation in RCC management, even as further studies on diverse RCC cell lines and real-world data are required.