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

Abstract

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.

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Acknowledgements

We thank Dr Julian Downward, Dr Richard Marais and Dr Maria Soengas for provision of Ras, B-Raf and Bax/Bak shRNA expression plasmids, respectively; Dr Eric Eldering for provision of shRNA constructs against Noxa and Mcl-1; Dr Dean Fennell for provision of H460 cells and for very useful discussions; Dr Yihong Ye for provision of shRNA constructs against ATF4 and Dr Hans van Dam for provision of shRNA constructs against Fra1 and ATF3. We thank Science Foundation Ireland (08/IN.1/B203) and The Irish Cancer Society (CRP08MAR) for support of this work. GB was supported, in part, by an IRCSET post-doctoral fellowship. CS was supported, in part, by an IRCSET PhD studentship. SJM is a Science Foundation Ireland Principal Investigator.

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Correspondence to S J Martin.

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Sheridan, C., Brumatti, G., Elgendy, M. et al. An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. Oncogene 29, 6428–6441 (2010). https://doi.org/10.1038/onc.2010.380

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  • DOI: https://doi.org/10.1038/onc.2010.380

Keywords

  • apoptosis
  • cisplatin
  • Noxa
  • BH3-only
  • ERK
  • Ras

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