Stress hormones increase cell proliferation and regulates interleukin-6 secretion in human oral squamous cell carcinoma cells

Abstract

Patients with oral cancer can have high psychological distress levels, but the effects of stress-related hormones on oral cancer cells and possible mechanisms underlying these relationships are unknown. In this study, we have investigated the effects of stress-related hormones on interleukin-6 (IL-6) secretion and proliferation of oral squamous cell carcinoma (OSCC) cells. The effects of norepinephrine (NE), and cortisol were studied in SCC9, SCC15, and SCC25 cells and effects of isoproterenol in SCC9 and SCC25 cells. Real-time PCR studies revealed constitutive β1- and β2-adrenergic receptors (β-ARs) expression in the SCC9, SCC15, and SCC25 cells. The results showed that NE and isoproterenol significantly enhanced IL-6 mRNA expression and protein production in supernatants of SCC9 and SCC25 cells. Physiological stress levels of NE and isoproterenol (10μM) at 1h elicited the most robust IL-6 increase. Regarding IL-6 secretion, 10μM NE induced a 5-fold increase at 1h, 3.7-fold increase at 6h, and 3.2-fold at 24h in SCC9 cells. These effects were blocked by the β-adrenergic antagonist propranolol, supporting a role for β-ARs in IL-6 secretion. The effects of cortisol varied according to the hormone concentration. Pharmacological concentrations of cortisol (1000nM) inhibited IL-6 production by SCC9 and SCC25 cells. Cortisol dose that simulates stress conditions (10nM) tended to increase IL-6 expression in SCC9 cells. Hormonal doses that simulate stress conditions (10μM NE, at 6h in SCC9 and SCC15 cells and 10nM cortisol, at 48h in SCC15 cells) stimulated increased cell proliferation. Treatment of SCC9 cells with IL-6 neutralizing ab (10μg/mL) partially inhibited NE-induced proliferation. Finally, 20 OSCC biopsies were shown to express β1- and β2-ARs. These findings suggest that stress hormones can affect oral cancer cells behavior.