Requirement for ERK Activation in Cisplatin-induced Apoptosis*

By Xiantao Wang, J. Martindale, N. Holbrook. Journal of Biological Chemistry, 2000

699 citations recorded by the source corpus.

Cisplatin activates multiple signal transduction pathways involved in coordinating cellular responses to stress. Here we demonstrate a requirement for extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase family in mediating cisplatin-induced apoptosis of human cervical carcinoma HeLa cells. Cisplatin treatment resulted in dose- and time- dependent activation of ERK. That elevated ERK activity contributed to cell death by cisplatin was supported by several observations: 1) PD98059 and U0126, chemical inhibitors of the MEK/ERK signaling pathway, prevented apoptosis; 2) pretreatment of cells with TPA, an activator of the ERK pathway, enhanced their sensitivity to cisplatin; 3) suramin, a growth factor receptor antagonist that greatly suppressed ERK activation, likewise inhibited cisplatin-induced apoptosis; and, finally, 4) HeLa cell variants selected for cisplatin resistance showed reduced activation of ERK following cisplatin treatment. Cisplatin-induced apoptosis was associated with cytochrome c release and subsequent caspase-3 activation, both of which could be prevented by treatment with the MEK inhibitors. However, the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone protected HeLa cells against apoptosis without affecting ERK activation. Taken together, our findings suggest that ERK activation plays an active role in mediating cisplatin-induced apoptosis of HeLa cells and functions upstream of caspase activation to initiate the apoptotic signal.

Subfields: Molecular Biology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/82accd749e82ef8eb88c4018774d5a758cae88b4

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In Molecular Biology

1. Guido Kroemer
2. L. Galluzzi
3. Oliver Kepp
4. M. Castedo
5. Dong Wang
6. Shuichan Xu
7. Zhimin Lu
8. S. Lippard

Citations in the corpus

• Molecular mechanisms of cisplatin resistance (2012, background): “…various branches of the mitogenactivated protein kinase (MAPK) system, including those mediated by extracellular signal-regulated kinases, c-JUN Oncogene N-terminal kinases and stress-activated protein kinases (Persons et al., 2000; Wang et al., 2000; Dent and Grant, 2001; Yeh et al., 2002).”
• ERK1/2 MAP kinases in cell survival and apoptosis (2006, background): “…of ERK2 activity has been reported to sensitize ovarian carcinoma cells to cisplatin-induced apoptosis ( 87, 88 ), but it has also been reported to induce drug resistance of cervical carcinoma cells to cisplatin ( 89, 90 ) and various other tumor cells to multiple anticancer drugs ( 85, 91, 92 ).”
• Cisplatin: mode of cytotoxic action and molecular basis of resistance (2003, background): “Studies by Wang et al. (2000) have demonstrated that all three kinase members are activated following exposure of tumor cells to cisplatin.”
• Cellular processing of platinum anticancer drugs (2005, background): “Cisplatin treatment results in dose- and time-dependent activation of ERK1/2 (Ref”