Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1910173 | Free Radical Biology and Medicine | 2008 | 10 Pages |
Abstract
Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd may induce neuronal apoptosis in part through activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2) pathways. However, the underlying mechanism remains enigmatic. Here we show that Cd induced generation of reactive oxygen species (ROS), leading to apoptosis of PC12 and SH-SY5Y cells. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged Cd-induced ROS, and prevented cell death, suggesting that Cd-induced apoptosis is attributed to its induction of ROS. Furthermore, we found that Cd-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), leading to activation of Erk1/2 and JNK, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented Cd-induced activation of Erk1/2 and JNK, as well as cell death. Cd-induced ROS was also linked to the activation of caspase-3. Pretreatment with inhibitors of JNK (SP600125) and Erk1/2 (U0126) partially blocked Cd-induced cleavage of caspase-3 and prevented cell death. However, zVAD-fmk, a pan caspase inhibitor, only partially prevented Cd-induced apoptosis. The results indicate that Cd induction of ROS inhibits PP2A and PP5, leading to activation of JNK and Erk1/2 pathways, and consequently resulting in caspase-dependent and -independent apoptosis of neuronal cells. The findings strongly suggest that the inhibitors of JNK, Erk1/2, or antioxidants may be exploited for prevention of Cd-induced neurodegenerative diseases.
Keywords
5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetateDAPIN-acetyl-l-cysteinePP2ANACPARPASK1PDLPP5CM-H2DCFDAMKP1zVAD-fmkFBSJnkDMEMPBS4′,6-diamidino-2-phenylindolec-Jun N-terminal kinaseDulbecco's modified Eagle MediumERK1/2MAPKMAPK kinaseMKKROSHydrogen peroxideamyotrophic lateral sclerosisAlzheimer's diseaseALSParkinson's diseaseApoptosisfetal bovine serumPhosphate-buffered salineH2O2protein phosphatase 2Aprotein phosphatase 5mitogen-activated protein kinasePropidium iodidepoly (ADP-ribose) polymerasePoly-d-lysineoptical densityCadmiumextracellular signal-regulated kinase 1/2apoptosis signal-regulating kinase 1Reactive oxygen species
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Authors
Long Chen, Lei Liu, Shile Huang,