Role of dipeptidyl peptidase 3 (DPP3) in cardiomyocyte toxicity induced by cancer cells and/or chemotherapy treatment

Abstract

Cardiotoxicity is an important side effect of chemotherapy such as Doxorubicin (Dox). Developing new biomarkers of cardiotoxicity is important to improve the cardiologic monitoring of cancer patients. Dipeptidyl peptidase 3 (DPP3), a zinc-dependent metallopeptidase, has emerged as a new biomarker and therapeutic target of acute cardiac dysfunction. Considering DPP3′ effects on cardiac function, and its increased expression in some types of cancer, we aimed to investigate a possible implication of DPP3 in cancer and/or chemotherapy induced cardiotoxicity. To evaluate DPP3 expression in cancer and in cardiomyocytes cell lines, the effect of DPP3 inhibition on cardiomyocytes survival and the effect of cancer cells secretome, in the presence or absence of DPP3, on cardiomyocytes survival. Our study was conducted, in vitro, in two cell lines: rat cardiomyocytes (H9C2) and murine ovarian cancer cells (ID8). Different treatments were applied; Dox (0.5 μM), DPP3 (0.62 or 6.2 μg/mL) alone or in combination with Dox, in addition to a treatment with anti-DPP3 antibody, procizumab PCZ (4 ng/mL). To investigate the direct effect of cancer on cardiomyocytes, the effect of ID8 secretome (non-treated, treated with Dox 0.5 μM, or with Dox 0.5 μM + PCZ 40 ng/mL), on cardiomyocytes was studied. Cell survival was evaluated after 24 h treatment. Finally, DPP3 protein expression was assessed by Western blot. Our results showed a significant decrease of H9C2 survival when treated with Dox 0.5 μM (×0.32, P < 0.05), reflecting its cardiotoxicity. DPP3 protein expression increased in both ID8 (×19, P < 0.05) and H9C2 (×3.5, P < 0.05) when treated with Dox. Treating ID8 with DPP3 0.62 μg/mL increased their survival when no treatment was applied (×1.52, P < 0.05), however, this increase was not significant with the higher concentration of DPP3. In the presence of Dox treatment, an increase of H9C2 survival was induced by DPP3, in both concentrations; 0.62 μg/mL (×1.68, P < 0.05), 62 μg/mL (×1.83, P < 0.05), in comparison to Dox alone. When blocking DPP3 by PCZ, the survival of H9C2, treated with Dox or with ID8 secretome treated with Dox, has increased (×1.71, P < 0.05) and (×1. 86, P < 0.05), respectively. The effect of PCZ on cardiotoxicity along aside with the increased expression of DPP3 induced by Dox may reflect a possible implication of DPP3 in Dox-induced cardiotoxicity.