Resveratrol prevents cadmium activation of Erk1/2 and JNK pathways from neuronal cell death via protein phosphatases 2A and 5

Abstract

Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative disorders. Resveratrol, a natural product, has been found to exert neuroprotective effects. However, little is known regarding the effect of resveratrol on Cd-evoked neurotoxicity. Here, we show that resveratrol effectively reversed Cd-elicited cell viability reduction, morphological change, nuclear fragmentation and condensation, as well as activation of caspase-3 in neuronal cells, implying neuroprotection against Cd-poisoning by resveratrol. Further research revealed that both c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases 1/2 (Erk1/2) were involved in the inhibitory effect of resveratrol on Cd-induced cell death, as selective inhibitors of Erk1/2 (U0126) and JNK (SP600125), or over-expression of dominant negative mitogen-activated protein kinase kinase 1 (MKK1) or dominant negative c-Jun potentiated resveratrol's prevention of Cd-induced phosphorylation of JNK and Erk1/2, as well as cell death in neuronal cells. Interestingly, resveratrol potently rescued the cells from Cd-induced suppression of protein phosphatases 2A (PP2A) and 5 (PP5) activity. Over-expression of PP2A or PP5 strengthened the inhibitory effects of resveratrol on Cd-induced activation of Erk1/2 and/or JNK, as well as cell death. The results indicate that resveratrol prevents Cd-induced activation of Erk1/ 2 and JNK pathways and neuronal cell death in part via activating PP2A and PP5. Our findings strongly support the notion that resveratrol may serve as a potential therapeutic agent in the prevention of Cd-induced neurodegenerative diseases. Keywords: cadmium, mitogen-activated protein kinase, neuronal cells, protein phosphatase 2A, protein phosphatase 5, resveratrol.

Early-Life Exposure to Lead Induces Cognitive Impairment in Elder Mice Targeting SIRT1 Phosphorylation and Oxidative Alterations

“…Recent study also illustrated that resveratrol effectively suppressed the decline of hippocampal pCREB, a downstream target of BDNF, after developmental Pb exposure (Feng et al, 2016). In addition, resveratrol also exhibits potent antioxidant capacity due to its ability to remove free radicals and metals and to activate endogenous antioxidant enzymes (Liu et al, 2015; Whitehouse et al, 2016). In view of this, we examined how resveratrol modulate a number of the pro-oxidant and anti-oxidant biomarker (MDA, GSH, GSH-Px, CAT, and 8-OHdG) on Pb-induced oxidative stress process in the present study.…”

PPP5C promotes cell proliferation and survival in human prostate cancer by regulating of the JNK and ERK1/2 phosphorylation

“…Knowing that PPP5C has certain relevance with MAPK pathways via ERK1/2, JNK, and P38, 29 – 31 we detected ERK, JNK, and P38 levels after PPP5C downregulation and found that the phosphorylation of ERK1/2 and JNK was significantly increased with the non-phosphorylation was fixed ( Figures 6 and 7 ). But whether the phosphorylation or the non-phosphorylation level of the P38 molecule was immovable when the PPP5C changed.…”

Resveratrol inhibits Erk1/2‐mediated adhesion of cancer cells via activating PP2A–PTEN signaling network

“…CN IV: collagen type IV; de-PP2A: demethylated-PP2A; Erk1/2: extracellular signal-regulated kinase 1/2; GFP: green fluorescent protein; IGF-1: insulin-like growth factor-1; mTOR: mechanistic/mammalian target of rapamycin; PP2A: protein phosphatase 2A; PTEN: phosphatase and tensin homolog; shRNA: short hairpin RNA; S6K1: S6 kinase 1 Resveratrol can inhibit Erk1/2 at high concentrations (Roy, Chen, Fu, Shankar, & Srivastava, 2011). Recently, we have noticed that resveratrol activates PP2A activity (C. Liu et al, 2015). This led us to ask whether resveratrol inhibits IGF-1-induced cancer cell adhesion by targeting PP2A-Erk1/2 pathway.…”

“…Importantly, PP2A, PTEN, and Akt function by regulating cell adhesion and migration (Haier & Nicolson, 2002;Kraus et al, 2002;Sontag & Sontag, 2006). In addition, studies have shown that resveratrol regulates PP2A, PTEN, and Akt (C. Liu et al, 2015;Y. Z. Liu et al, 2014).…”