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Celastrol Attenuates Cadmium‐Induced Neuronal Apoptosis via Inhibiting Ca 2+ ‐CaMKII‐Dependent Akt/mTOR Pathway
Author(s) -
Zhang Ruijie,
Zhu Yu,
Dong Xiaoqing,
Liu Beibei,
Zhang Nana,
Wang Xiaoxue,
Liu Lei,
Xu Chong,
Huang Shile,
Chen Long
Publication year - 2017
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25703
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , apoptosis , cadmium , celastrol , chemistry , microbiology and biotechnology , signal transduction , cancer research , biology , biochemistry , organic chemistry
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.