Selenium mitigates cadmium-induced crosstalk between autophagy and endoplasmic reticulum stress via regulating calcium homeostasis in avian leghorn male hepatoma (LMH) cells

Abstract

Cadmium (Cd) is a toxic heavy metal and widespread in environment and food, which is adverse to human and animal health. Food intervention is a hot topic because it has no side effects. Selenium (Se) is an essential trace element, found in various fruits and vegetables. Many previous papers have described that Se showed ameliorative effects against Cd. However, the underlying mechanism of antagonistic effect of Se against Cd-induced cytotoxicity in avian leghorn male hepatoma (LMH) cells is unknown, the molecular mechanism of Se antagonistic effect on Cd-induced and calcium (Ca²⁺) homeostasis disorder and crosstalk of ER stress and autophagy remain to be explored. In order to confirm the antagonistic effect of Se on Cd-induced LMH cell toxicity, LMH cells were treated with CdCl₂ (2.5 μM) and Na₂SeO₃ (1.25 and 2.5 μM) for 24 h. In this study, Cd exposure induced cell death, disrupted intracellular Ca²⁺ homeostasis and Ca²⁺ homeostasis related regulatory factors, interfered with the cycle of cadherin (CNX)/calreticulin (CRT), and triggered ER stress and autophagy. Se intervention inhibited Cd-induced LDH release and crosstalk of ER stress and autophagy via regulating intracellular Ca²⁺ homeostasis. Moreover, Se mitigated Cd-induced Intracellular Ca²⁺ overload by Ca²⁺/calmodulin (CaM)/calmodulin kinase IV (CaMK-IV) signaling pathway. Herein, CNX/CRT cycle played a critical role for the protective effect of Se on Cd-induced hepatotoxicity. Based on these findings, we demonstrated that the application of Se is beneficial for prevention and alleviation of Cd toxicity.

Keywords: Autophagy; Ca(2+) homeostasis; Cadmium; ER stress; Selenium.