Celastrol Attenuates Cadmium‐Induced Neuronal Apoptosis via Inhibiting Ca2+‐CaMKII‐Dependent Akt/mTOR Pathway. Issue 8 (28th February 2017)

• Record Type: Journal Article
• Authors: Zhang, Ruijie; Zhu, Yu; Dong, Xiaoqing; Liu, Beibei; Zhang, Nana; Wang, Xiaoxue; Liu, Lei; Xu, Chong; Huang, Shile; Chen, Long
• Is Part Of: Journal of cellular physiology. Volume 232:Issue 8(2017:Aug.)
• Page Start: 2145
• Page End: 2157
• Publication Date: 2017-02-28
• Subjects: Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.25703
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : Cadmium (Cd), an environmental and industrial pollutant, affects the nervous system and consequential neurodegenerative disorders. Recently, we have shown that celastrol prevents Cd‐induced neuronal cell death partially by suppressing Akt/mTOR pathway. However, the underlying mechanism remains to be elucidated. Here, we show that celastrol attenuated Cd‐elevated intracellular‐free calcium ([Ca 2+ ]i ) level and apoptosis in neuronal cells. Celastrol prevented Cd‐induced neuronal apoptosis by inhibiting Akt‐mediated mTOR pathway, as inhibition of Akt with Akt inhibitor X or ectopic expression of dominant negative Akt reinforced celastrol's prevention of Cd‐induced phosphorylation of S6K1/4E‐BP1 and cell apoptosis. Furthermore, chelating intracellular Ca 2+ with BAPTA/AM or preventing [Ca 2+ ]i elevation using EGTA potentiated celastrol's repression of Cd‐induced [Ca 2+ ]i elevation and consequential activation of Akt/mTOR pathway and cell apoptosis. Moreover, celastrol blocked Cd‐elicited phosphorylation of CaMKII, and pretreatment with BAPTA/AM or EGTA enhanced celastrol's suppression of Cd‐increased phosphorylation of CaMKII in neuronal cells, implying that celastrol hinders [Ca 2+ ]i ‐mediated CaMKII phosphorylation. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of Akt/mTOR pathway and cell apoptosis, and this was strengthened by celastrol. Taken together, these data demonstrate that celastrol attenuates Cd‐induced neuronal apoptosis via inhibiting Ca 2+ ‐CaMKII‐dependent Akt/mTOR pathway. Our findings underscore that celastrol may act as a neuroprotective agent for the prevention of Cd‐induced neurodegenerative disorders. J. Cell. Physiol. 232: 2145–2157, 2017. © 2016 Wiley Periodicals, Inc. Abstract : Celastrol prevents Cd‐induced elevation of [Ca 2+ ]i, which results in inhibition of CaMKII phosphorylation. This leads to suppression of CaMKII‐dependent Akt/mTOR pathway, thereby preventing Cd‐induced apoptosis in neuronal cells.