Abstract
BackgroundCardiac dysfunction including arrhythmias appear frequently in patients with cancers, which are expected to be caused mainly by cardiotoxic effects of chemotherapy. Experimental studies investigating the effects of cancer cell secretion without chemotherapy on ion channel function in human cardiomyocytes are still lacking.MethodsThe human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from three healthy donors were treated with gastrointestinal (GI) cancer (AGS and SW480 cells) medium for 48 h. The qPCR, patch-clamp, western blotting, immunostaining, dot blotting, bisulfite sequence, and overexpression of the ten-eleven translocation (TET) enzyme were performed for the study.ResultsAfter treated with cancer cell secretion, the maximum depolarization velocity and the action potential amplitude were reduced, the action potential duration prolonged, peak Na+ current, and the transient outward current were decreased, late Na+ and the slowly activating delayed rectifier K+ current were increased. Changes of mRNA and protein level of respective channels were detected along with altered DNA methylation level in CpG island in the promoter regions of ion channel genes and increased protein levels of DNA methyltransferases. Phosphoinositide 3-kinase (PI3K) inhibitor attenuated and transforming growth factor-β (TGF-β) mimicked the effects of cancer cell secretion.ConclusionsGI cancer cell secretion could induce ion channel dysfunction, which may contribute to occurrence of arrhythmias in cancer patients. The ion channel dysfunction could result from DNA methylation of ion channel genes via activation of TGF-β/PI3K signaling. This study may provide new insights into pathogenesis of arrhythmia in cancer patients.
Highlights
Cardiac dysfunction including arrhythmias appear frequently in patients with cancers, which are expected to be caused mainly by cardiotoxic effects of chemotherapy
To examine possible effects of cancer cells on the electrophysiological characteristics of cardiomyocytes, the action potentials (APs) of human-induced pluripotent stem cells (hiPSCs)-CMs were measured after cancer cell secretion treatment (Figure 1)
The maximum depolarization velocity (Vmax) and the action potential amplitude (APA) were reduced and the action potential duration at 10% repolarization (APD10) prolonged in AGS group compared with control and medium groups
Summary
Cardiac dysfunction including arrhythmias appear frequently in patients with cancers, which are expected to be caused mainly by cardiotoxic effects of chemotherapy. Cardiovascular disease (CVD) and cancer are the two most common causes of mortality worldwide [1]. A study demonstrated that heart rate variability and cardiorespiratory coordination were changed in patients with breast cancer [8]. Another study on acute leukemia patients found that cardiac autonomic functions were changed with a decrease in heart rate variability [9]. These findings further demonstrate that, apart from anticancer toxicity, a tumor may itself have a deleterious effect on myocardial function of the heart. The aforementioned evidence indicates that cancer may affect the electrophysiology of cardiomyocytes, independent of cancer therapy
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