Stress hormones promote DNA damage in human oral keratinocytes

• Published in: Scientific reports Vol. 11; no. 1; pp. 19701 - 11
• Main Authors: Valente, Vitor Bonetti, de Melo Cardoso, Diovana, Kayahara, Giseli Mitsuy, Nunes, Giovana Barros, Tjioe, Kellen Cristine, Biasoli, Éder Ricardo, Miyahara, Glauco Issamu, Oliveira, Sandra Helena Penha, Mingoti, Gisele Zoccal, Bernabé, Daniel Galera
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.10.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 631/67/1536; 631/67/1665; 631/80; 692/4028/67; 8-Hydroxy-2'-Deoxyguanosine - metabolism; Adrenergic receptors; Apoptosis; Carcinogenesis; Carcinogens; Deoxyribonucleic acid; DNA; DNA Breaks - drug effects; DNA damage; DNA Damage - drug effects; DNA-formamidopyrimidine glycosylase; Epithelial Cells; Genotoxicity; Glucocorticoids; Histones - metabolism; Hormones; Hormones - metabolism; Hormones - pharmacology; Humanities and Social Sciences; Humans; Hydrocortisone - pharmacology; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Mouth Mucosa - metabolism; multidisciplinary; Nicotiana - chemistry; Nitrosamines - chemistry; Nitrosamines - pharmacology; Norepinephrine; Norepinephrine - pharmacology; Oxidation; Oxidation-Reduction; Propranolol; Science; Science (multidisciplinary); Stress, Physiological
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-99224-w

Chronic stress increases the systemic levels of stress hormones norepinephrine and cortisol. As well as tobacco-specific carcinogen NNK (4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone), they can induce expressive DNA damage contributing to the cancer development. However, it is unknown whether stress hormones have genotoxic effects in oral keratinocytes. This study investigated the effects of stress hormones on DNA damage in a human oral keratinocyte cell line (NOK-SI). NOK-SI cells stimulated with norepinephrine or cortisol showed higher DNA damage compared to untreated cells. Norepinephrine-induced DNA damage was reversed by pre-treatment with beta-adrenergic blocker propranolol. Cells treated with NNK combined to norepinephrine displayed reduced levels of caspases 3 and 7. Cortisol also reduced the activity of pro-apoptotic enzymes. NNK or norepinephrine promoted single-strand breaks and alkali-label side breaks in the DNA of NOK-SI cells. Pre-treatment of cells with propranolol abolished these effects. Carcinogen NNK in the presence or absence of cortisol also induced DNA damage of these cells. The genotoxic effects of cortisol alone and hormone combined with NNK were blocked partially and totally, respectively, by the glucocorticoid receptor antagonist RU486. DNA damage promoted by NNK or cortisol and carcinogen combined to the hormone led to intracellular γH2AX accumulation. The effects caused by NNK and cortisol were reversed by propranolol and glucocorticoid receptor antagonist RU486, respectively. Propranolol inhibited the oxidation of basis induced by NNK in the presence of DNA-formamidopyrimidine glycosylase. DNA breaks induced by norepinephrine in the presence or absence of NNK resulted in higher 8OHdG cellular levels. This effect was also induced through beta-adrenergic receptors. Together, these findings indicate that stress hormones induce DNA damage of oral keratinocytes and could contribute to oral carcinogenesis.