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

作者：Sheridan C; Brumatti G; Elgendy M; Brunet M; Martin S J^*

来源：Oncogene, 2010, 29(49): 6428-6441.

DOI：10.1038/onc.2010.380

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

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. Oncogene (2010) 29, 6428-6441; doi:10.1038/onc.2010.380; published online 30 August 2010

• 出版日期2010-12