MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis

J Neurochem. 2008 Apr;105(1):251-61. doi: 10.1111/j.1471-4159.2007.05133.x. Epub 2007 Nov 16.


Cadmium (Cd) may be accumulated in human body through long-term exposure to Cd-polluted environment, resulting in neurodegeneration and other diseases. To study the mechanism of Cd-induced neurodegeneration, PC12 and SH-SY5Y cells were exposed to Cd. We observed that Cd-induced apoptosis in the cells in a time- and concentration-dependent manner. Cd rapidly activated the mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38. Inhibition of Erk1/2 and JNK, but not p38, partially protected the cells from Cd-induced apoptosis. Consistently, over-expression of dominant negative c-Jun or down-regulation of Erk1/2, but not p38 MAPK, partially prevented Cd-induced apoptosis. To our surprise, Cd also activated mammalian target of rapamycin (mTOR)-mediated signaling pathways. Treatment with rapamycin, an mTOR inhibitor, blocked Cd-induced phosphorylation of S6K1 and eukaryotic initiation factor 4E binding protein 1, and markedly inhibited Cd-induced apoptosis. Down-regulation of mTOR by RNA interference also in part, rescued cells from Cd-induced death. These findings indicate that activation of the signaling network of MAPK and mTOR is associated with Cd-induced neuronal apoptosis. Our results strongly suggest that inhibitors of MAPK and mTOR may have a potential for prevention of Cd-induced neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cadmium / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mitogen-Activated Protein Kinase Kinases / physiology*
  • Neuroblastoma
  • Neurons / drug effects*
  • PC12 Cells
  • Propidium
  • Protein Kinases / metabolism*
  • Rats
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases
  • Transfection / methods


  • Enzyme Inhibitors
  • Cadmium
  • Propidium
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase Kinases