We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Anti-apoptotic effects of protein kinase C-delta and c-fos in cisplatin-treated thyroid cells.
- Authors
Muscella, Antonella; Urso, Loredana; Calabriso, Nadia; Vetrugno, Carla; Rochira, Alessio; Storelli, Carlo; Marsigliante, Santo
- 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.
- 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
- Publication
British Journal of Pharmacology, 2009, Vol 156, Issue 5, p751
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1111/j.1476-5381.2008.00049.x