Differential effects of p38 and JNK activation by GSK3 on cadmium-induced autophagy and apoptosis

作者：Jung Ki Tae^*; Kim Hak Ryul; Lee Byung Hoon; Kim Seong Hwan; So Keum Young; An Tae Hun; Lee Hyun Young; Oh Seon Hee

来源：Toxicology Research, 2015, 4(4): 976-985.

DOI：10.1039/c5tx00007f

Cadmium (Cd) toxicity is associated with endoplasmic reticulum (ER) stress-mediated apoptosis and autophagy. However, the regulatory mechanisms responsible for the signaling pathways initiated by Cd are incompletely understood. Here, we investigated the involvement of glycogen synthase kinase (GSK) 3 alpha beta and mitogen-activated protein kinases (MAPKs) in Cd toxicity. Cd-exposed H460 cells exhibited activation of JNK, p38, PERK, and CHOP and induction of autophagy and apoptosis; in contrast, levels of these proteins were minimal in Cd-resistant H1299 cells. In H460 cells, genetic or pharmacological inhibition of JNK markedly enhanced CHOP, autophagy and apoptosis induced by Cd, which were reversed by overexpression of JNK1. Inhibition of p38 suppressed Cd-induced CHOP, and markedly inhibited autophagy via Atg5 downregulation. Cd-exposed H460 cells showed GSK3 alpha beta phosphorylation at serine (Ser) and tyrosine (Tyr) residues, which was downregulated by a GSK3 inhibitor (SB216763) and by genetic silencing of GSK3 alpha, subsequently suppressing JNK and p38 activation. However, H460 cells pretreated with lithium or overexpressing GSK3 alpha exhibited enhanced JNK and p38 activation. Pretreatment of H460 cells with okadaic acid (a Ser/Thr phosphatase inhibitor) upregulated Cd-induced p-Ser GSK3 alpha beta and enhanced CHOP, p-p38 and autophagy, whereas treatment with vanadate (a tyrosine phosphatase inhibitor) downregulated Cd-induced p-Ser GSK3 alpha beta, enhanced p-JNK and downregulated CHOP and autophagy. Furthermore, H460 cells overexpressing a constitutively active GSK3 beta mutant (S9A) exhibited enhanced p-JNK and inhibited CHOP, whereas overexpression of constitutively inactive GSK3 beta (K85A) enhanced p-p38 and autophagy in response to Cd. Pretreatment with N-acetyl cysteine suppressed Cdinduced p-Ser/p-Tyr GSK3 alpha beta and downstream pathways. These findings show that Cd toxicity is regulated by autophagy, which can be countered by prosurvival JNK and prodeath p38 MAPK activation through site-specific phosphorylation of GSK3 alpha beta.

• 出版日期2015