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Anti-apoptotic effects of protein kinase C-delta and c-fos in cisplatin-treated thyroid cells.
- Source :
- British Journal of Pharmacology; Mar2009, Vol. 156 Issue 5, p751-763, 13p, 4 Black and White Photographs, 6 Graphs
- Publication Year :
- 2009
-
Abstract
- <bold>Background and Purpose: </bold>We showed previously that cisplatin inititates a signalling pathway mediated by PKC-delta/extracellular signal-regulated kinase (ERK), important for maintaining viability in PC Cl3 thyroid cells. The studies described herein examined whether c-fos was associated with cisplatin resistance and the signalling link between c-fos and PKC-delta/ERK.<bold>Experimental Approach: </bold>Cells were treated with various pharmacological inhibitors of PKCs and ERK, or were depleted of c-fos, PKC-delta, PKC-epsilon and caspase-3 by small interfering RNA (siRNA), then incubated with cisplatin and cytotoxicity assessed.<bold>Key Results: </bold>Cisplatin provokes the induction of c-fos and the activation of conventional PKC-beta, and novel PKC-delta and -epsilon. The cisplatin-provoked c-fos induction was decreased by Gö6976, a PKC-beta inhibitor; by siRNA for PKC-delta- but not that for PKC-epsilon or by PD98059, a mitogen-activated protein kinase/ERK kinase inhibitor. Expression of c-fos was abolished by GF109203X, an inhibitor of all PKC isoforms, or by PD98059 plus Gö6976 or by PKC-delta-siRNA plus Gö6976. When c-fos expression was blocked by siRNA, cisplatin cytotoxicity was strongly enhanced with increased caspase-3 activation. In PKC-delta-depleted cells treated with cisplatin, caspase-3 activation was increased and cell viability decreased. In these PKC-delta-depleted cells, PD98059 did not affect caspase-3 activation.<bold>Conclusions and Implications: </bold>In PC Cl3 cells, in the cell signalling pathways that lead to cisplatin resistance, PKC-delta controls ERK activity and, together with PKC-beta, also the induction of c-fos. Hence, the protective role of c-fos in thyroid cells has the potential to provide new opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Subjects :
- ANTINEOPLASTIC agents
CISPLATIN
ALKYLATING agents
PROTEIN kinases
RNA
PROTEINS
CELL differentiation
BIOCHEMISTRY
APOPTOSIS
CELL physiology
RATS
ISOENZYMES
CELLULAR signal transduction
PHENOMENOLOGY
TRANSFERASES
CELL lines
THYROID gland
DRUG resistance in cancer cells
ANIMALS
PHARMACODYNAMICS
CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 156
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 43882114
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2008.00049.x