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Agnieszka Kosowska Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Enrique Gallego-Colon Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Wojciech Garczorz Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Agnieszka Kłych-Ratuszny Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Mohammad Reza F Aghdam Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Michał Woz´niak Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Andrzej Witek Department of Gynaecology and Obstetrics, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Agnieszka Wróblewska-Czech Department of Gynaecology and Obstetrics, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Anna Cygal Department of Gynaecology and Obstetrics, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Jerzy Wojnar Department of Internal Medicine and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Tomasz Francuz Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

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Diabetes and cancer are prevalent diseases whose incidence is increasing globally. Diabetic women have a moderate risk increase in ovarian cancer, suggested to be due to an interaction between these two disorders. Furthermore, patients manifesting both diseases have associated worse prognosis, reduced survival and shorter relapse-free survival. According to current recommendations, incretin drugs such as Exenatide, a synthetic analog of Exendin-4, and Liraglutide are used as therapy for the type 2 diabetes (T2D). We studied the effects of GLP-1 and Exendin-4 on migration, apoptosis and metalloproteinase production in two human ovarian cancer cells (SKOV-3 and CAOV-3). Exendin-4 inhibited migration and promoted apoptosis through caspase 3/7 activation. Exendin-4 also modulated the expression of key metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). Vascular endothelial cells, which contribute to the formation and progression of metastasis, were also analyzed. TNF-α-stimulated endothelial cells from iliac artery after Exendin-4 treatment showed reduced production of adhesion molecules (ICAM-1 and VCAM-1). Additionally, incretin treatment inhibited activation of apoptosis in TNF-α-stimulated endothelial cells. In the same experiment, MMPs (MMP-1 and MMP-9), which are relevant for tumor development, were also reduced. Our study demonstrated that incretin drugs may reduce cancer cell proliferation and dissemination potential, hence limiting the risk of metastasis in epithelial ovarian cancer.

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