Abstract
3-deazaneplanocin A (3-DZNeP) has been used as an inhibitor of enhancer of zeste homolog 2 (EZH2). Here, we explore the role and underlying mechanisms action of 3-DZNeP in abrogating cisplatin nephrotoxicity. Exposure of cultured mouse renal proximal tubular epithelial cells (mTECs) to cisplatin resulted in dose and time-dependent cleavage of caspase-3, decrease of cell viability, and increase of histone H3 lysine 27 trimethylation (H3K27me3), whereas expression levels of EZH2, a major methyltransferase of H3K27me3, were not affected. Treatment with 3-DZNeP significantly inhibited cisplatin-induced activation of caspase-3, apoptosis, loss of cell viability but did not alter levels of EZH2 and H3K27me3 in cultured mTECs. 3-DZNeP treatment did not affect activation of extracellular signal-regulated kinase (ERK) 1/2, p38 or c-Jun N-terminal kinases (JNK) 1/2, which contribute to renal epithelial cell death, but caused dose-dependent restoration of E-cadherin in mTECs exposed to cisplatin. Silencing of E-cadherin expression by siRNA abolished the cytoprotective effects of 3-DZNeP. In contrast, 3-DZNeP treatment potentiated the cytotoxic effect of cisplatin in H1299, a non-small cell lung cancer cell line that expresses lower E-cadherin levels. Finally, administration of 3-DZNeP attenuated renal dysfunction, morphological damage, and renal tubular cell death, which was accompanied by E-cadherin preservation, in a mouse model of cisplatin nephrotoxicity. Overall, these data indicate that 3-DZNeP suppresses cisplatin-induced tubular epithelial cell apoptosis and acute kidney injury via an E-cadherin-dependent mechanism, and suggest that combined application of 3-DZNeP with cisplatin would be a novel chemotherapeutic strategy that enhances the anti-tumor effect of cisplatin and reduces its nephrotoxicity.
Highlights
Acute kidney injury (AKI) characterized by abrupt deterioration in kidney function and tubular cell death is associated with high morbidity and mortality[1]
Our results demonstrated that 3-deazaneplanocin A (3-DZNeP) protects against cisplatin-induced tubular cell injury in cultured mouse renal proximal tubular epithelial cells and in a mouse model of cisplatin nephrotoxicity and enhances the cytotoxic effect of cisplatin in tumor cells (i.e. non-small cell lung cancer (NSCLC) cells) through a mechanism involving the upregulation of E-cadherin expression
Knockdown of enhancer of zeste homolog 2 (EZH2) enhances cisplatin-induced tubular cell apoptosis To validate the role of EZH2 in cisplatin-induced tubular cell apoptosis, we further examined the effect of EZH2 silencing on caspase 3-cleavege, cell viability, and chromatin condensation in mouse renal proximal tubular epithelial cells (mTECs)
Summary
Acute kidney injury (AKI) characterized by abrupt deterioration in kidney function and tubular cell death is associated with high morbidity and mortality[1]. It can be caused by multiple pathological conditions, such as Nephrotoxic AKI constitute approximately one-third of patients with AKI3. Among the nephrotoxic agents that induce AKI, cisplatin (dichlorodiamino platinum), a chemotherapeutic drug that has been extensively used in chemotherapy, is most investigated in vitro and in vivo models of AKI. One-third of patient undergoing cisplatin treatment suffers from this disorder, and there is no effective therapeutic strategy to protect against its nephrotoxicity currently[6,10]. Finding agents that can ameliorate cisplatin-induced AKI is a critical challenge given its widespread use as chemotherapy
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