An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs

Oncogene. 2010 Dec 9;29(49):6428-41. doi: 10.1038/onc.2010.380. Epub 2010 Aug 30.


Cisplatin is a widely used cancer chemotherapeutic that promotes DNA damage-associated apoptosis. Although platinum compounds are known to form DNA adducts and provoke DNA damage, the molecular mechanism of cisplatin-induced cell death remains unclear. In this article, we show that the BH3-only protein Noxa is strongly transcriptionally upregulated in response to cisplatin and related platinum compounds. Cisplatin-induced Noxa expression was ERK dependent, but p53 independent, and inhibition of ERK activation markedly attenuated cisplatin-induced cell death, as well as Noxa expression. Furthermore, siRNA-mediated ablation of Noxa expression also inhibited cisplatin-induced cell death and permitted clonogenic survival. These observations reveal a novel ERK-regulated route to Noxa expression that is important for the cell killing activity of platinum-based chemotherapeutic drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • Cisplatin / pharmacology*
  • DNA Damage
  • Extracellular Signal-Regulated MAP Kinases / analysis
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • HeLa Cells
  • Humans
  • Leupeptins / pharmacology
  • Platinum Compounds / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • Leupeptins
  • PMAIP1 protein, human
  • Platinum Compounds
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • Extracellular Signal-Regulated MAP Kinases
  • Cisplatin
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde