Journal
ONCOGENE
Volume 25, Issue 20, Pages 2909-2919Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209312
Keywords
glioblastoma; protein kinase C iota; glia maturation factor beta; p38 MAP kinase; cisplatin
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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 ( PKC iota andPKC zeta) 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 PKC iota. Transfection of cells with either of two different RNA duplexes specific for PKC iota causeda partial sensitisation to cell death induced by the chemotherapy agent cisplatin. To screen for possible mechanisms for PKC iota- mediated chemoresistance, microarray analysis of gene expression was performed on RNA from glioblastoma cells that were either untreated or depleted of PKC iota. This identified sets of genes that were regulated either positively or negatively by PKC iota. Within the set of genes that were negatively regulated by PKC iota, the function of the gene coding for GMF beta, 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 GMFb mRNA and protein increased upon PKC iota depletion, and this was accompanied by an increase in cisplatin- activated p38 MAP kinase signaling. Transient overexpression of GMFb increased cisplatin-activated p38 MAP kinase signaling and also sensitised cells to cisplatin cytotoxicity. The increase in cisplatin cytotoxicity seen with PKCi depletion was blocked by the p38 MAP kinase inhibitor SKF86002. These data show that PKCi can confer partial resistance to cisplatin in glioblastoma cells by suppressing GMF beta- mediated enhancement of p38 MAP kinase signaling.
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