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

C Sheridan, G Brumatti, M Elgendy, M Brunet… - Oncogene, 2010 - nature.com
C Sheridan, G Brumatti, M Elgendy, M Brunet, SJ Martin
Oncogene, 2010nature.com
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 …
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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