| Autor: |
Baldwin, R. M., Garratt-Lalonde, M., Parolin, D. A. E., Krzyzanowski, P. M., Andrade, M. A., Lorimer, I. A. J. |
| Předmět: |
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| Zdroj: |
Oncogene; 5/11/2006, Vol. 25 Issue 20, p2909-2919, 11p, 2 Black and White Photographs, 1 Chart, 5 Graphs |
| Abstrakt: |
Glioblastoma multiforme is an aggressive form of brain cancer that responds poorly to chemotherapy and is generally incurable. The basis for the poor response of this cancer to chemotherapy is not well understood. The atypical protein kinases C (PKCι and PKCζ) have previously been implicated in leukaemia cell chemoresistance. To assess the role of atypical PKC in glioblastoma cell chemoresistance, RNA interference was used to deplete human glioblastoma cells of PKCι. Transfection of cells with either of two different RNA duplexes specific for PKCι caused a partial sensitisation to cell death induced by the chemotherapy agent cisplatin. To screen for possible mechanisms for PKCι-mediated chemoresistance, microarray analysis of gene expression was performed on RNA from glioblastoma cells that were either untreated or depleted of PKCι. This identified sets of genes that were regulated either positively or negatively by PKCι. Within the set of genes that were negatively regulated by PKCι, the function of the gene coding for GMFβ, an enhancer of p38 mitogen-activated protein kinase (MAP kinase) signaling, was investigated further, as the p38 MAP kinase pathway has been previously identified as a key mediator of cisplatin cytotoxicity. The expression of both GMFβ mRNA and protein increased upon PKCι depletion, and this was accompanied by an increase in cisplatin-activated p38 MAP kinase signaling. Transient overexpression of GMFβ increased cisplatin-activated p38 MAP kinase signaling and also sensitised cells to cisplatin cytotoxicity. The increase in cisplatin cytotoxicity seen with PKCι depletion was blocked by the p38 MAP kinase inhibitor SKF86002. These data show that PKCι can confer partial resistance to cisplatin in glioblastoma cells by suppressing GMFβ-mediated enhancement of p38 MAP kinase signaling.Oncogene (2006) 25, 2909–2919. doi:10.1038/sj.onc.1209312; published online 12 December 2005 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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