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Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5.
Free Radic Biol Med. 2008 Oct 01; 45(7):1035-44.FR

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18703135

Citation

Chen, Long, et al. "Cadmium Activates the Mitogen-activated Protein Kinase (MAPK) Pathway Via Induction of Reactive Oxygen Species and Inhibition of Protein Phosphatases 2A and 5." Free Radical Biology & Medicine, vol. 45, no. 7, 2008, pp. 1035-44.
Chen L, Liu L, Huang S. Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5. Free Radic Biol Med. 2008;45(7):1035-44.
Chen, L., Liu, L., & Huang, S. (2008). Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5. Free Radical Biology & Medicine, 45(7), 1035-44. https://doi.org/10.1016/j.freeradbiomed.2008.07.011
Chen L, Liu L, Huang S. Cadmium Activates the Mitogen-activated Protein Kinase (MAPK) Pathway Via Induction of Reactive Oxygen Species and Inhibition of Protein Phosphatases 2A and 5. Free Radic Biol Med. 2008 Oct 1;45(7):1035-44. PubMed PMID: 18703135.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5. AU - Chen,Long, AU - Liu,Lei, AU - Huang,Shile, Y1 - 2008/07/26/ PY - 2008/06/02/received PY - 2008/07/12/revised PY - 2008/07/16/accepted PY - 2008/8/16/pubmed PY - 2008/11/5/medline PY - 2008/8/16/entrez SP - 1035 EP - 44 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 45 IS - 7 N2 - 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. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/18703135/Cadmium_activates_the_mitogen_activated_protein_kinase__MAPK__pathway_via_induction_of_reactive_oxygen_species_and_inhibition_of_protein_phosphatases_2A_and_5_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(08)00435-8 DB - PRIME DP - Unbound Medicine ER -