Abstract
We have previously shown that protein kinase C (PKC) acts upstream of caspases to regulate cisplatin-induced apoptosis. Since extracellular signal-regulated kinases (ERKs) have also been implicated in DNA damage-induced apoptosis, we have examined if ERK signaling pathway acts downstream of PKC in the regulation of cisplatin-induced apoptosis. PKC activator PDBu induced ERK1/2 phosphorylation which was inhibited by general PKC inhibitor bisindolylmaleimide and Gö 6983 as well as the MEK inhibitor U0126 but not by the PKCδ inhibitor rottlerin. Cisplatin caused a concentration- dependent activation of ERK1/2 in HeLa cells. The level of ERK2 was decreased in HeLa cells that acquired resistance to cisplatin (HeLa/CP). The MEK inhibitor U0126 inhibited cisplatin-induced ERK activation and attenuated cisplatin-induced cell death. Inhibition of PKCδ by rottlerin or depletion of PKCδ by siRNA inhibited cisplatin-induced ERK activation. These results suggest that cisplatin-induced DNA damage results in activation of ERK1/2 via PKCδ.
Original language | English |
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Pages (from-to) | 1068-1073 |
Number of pages | 6 |
Journal | Biochemical and Biophysical Research Communications |
Volume | 334 |
Issue number | 4 |
DOIs | |
State | Published - 9 Sep 2005 |
Keywords
- Apoptosis
- Cisplatin
- DNA damage
- Drug-resistance
- ERK
- HeLa cells
- PKCδ
- Rottlerin
- U0126
- siRNA