Norepinephrine-Induced DNA Damage in Ovarian Cancer Cells.

Rocio Lamboy-Caraballo,Alvaro N.A Monteiro,Arelis Acevedo-Santiago,Jaime Matta,Guillermo N Armaiz-Pena,Carmen Ortiz-Sanchez

doi:10.3390/ijms21062250

Abstract

Multiple studies have shown that psychological distress in epithelial ovarian cancer (EOC) patients is associated with worse quality of life and poor treatment adherence. This may influence chemotherapy response and prognosis. Moreover, although stress hormones can reduce cisplatin efficacy in EOC treatment, their effect on the integrity of DNA remains poorly understood. In this study, we investigated whether norepinephrine and epinephrine can induce DNA damage and modulate cisplatin-induced DNA damage in three EOC cell lines. Our data show that norepinephrine and epinephrine exposure led to increased nuclear γ-H2AX foci formation in EOC cells, a marker of double-strand DNA breaks. We further characterized norepinephrine-induced DNA damage by subjecting EOC cells to alkaline and neutral comet assays. Norepinephrine exposure caused DNA double-strand breaks, but not single-strand breaks. Interestingly, pre-treatment with propranolol abrogated norepinephrine-induced DNA damage indicating that its effects may be mediated by β-adrenergic receptors. Lastly, we determined the effects of norepinephrine on cisplatin-induced DNA damage. Our data suggest that norepinephrine reduced cisplatin-induced DNA damage in EOC cells and that this effect may be mediated independently of β-adrenergic receptors. Taken together, these results suggest that stress hormones can affect DNA integrity and modulate cisplatin resistance in EOC cells.

Highlights

Epithelial ovarian cancer (EOC) has one of the highest worldwide mortality rates among cancers of the female reproductive system [1]
We examined the ability of two catecholamines to induce single- or double-strand DNA damage, as well as the effect of NE in cisplatin-induced DNA damage in ovarian cancer cells
To explore whether NE induced single-strand or double-strand DNA damage in EOC cells in a dose-dependent manner, COV362 and SKOV3 cells were treated with increasing concentrations of NE (0.1, 1, 10, and 100 μM) for 24 h

Summary

Introduction

Epithelial ovarian cancer (EOC) has one of the highest worldwide mortality rates among cancers of the female reproductive system [1]. Poor survival rates and the limited efficacy of current therapies make uncovering novel molecular pathways involved in EOC a top priority. Altered psychological states, such as chronic stress or depression, affect the quality of life of EOC patients and can promote tumor progression and influence treatment outcomes [3,4,5,6,7,8,9]. Several studies show that chronic stress correlates with elevated levels of systemic norepinephrine (NE) [12,13], increased EOC risk [14,15], and reduced chemotherapy efficacy [16,17,18]. In EOC, sustained adrenergic signaling is associated with increased inflammatory responses, tumor growth, invasiveness, and evasion of apoptotic processes [19,20,21,22,23,24,25,26,27]

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Results

Conclusion