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Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells

Oncogene volume 22, pages 7617–7627 (2003)Cite this article

Abstract

Activation of Akt signalling pathway is frequently found in glioma cells and may contribute to their resistance to undergo apoptosis in response to conventional therapies. We found that cyclosporin A (CsA) induces apoptosis of C6 glioma cells, which is associated with transcriptional activation of fasL. In the present paper, we investigated an involvement of Akt signalling in the regulation of FasL expression in CsA-induced apoptosis. We demonstrated that the level of active Akt decreases significantly after CsA treatment, which results in the decrease of Forkhead phosphorylation and its translocation to the nucleus. It correlated with an increase of binding to the Forkhead-responsive element FHRE from the FasL promoter, as demonstrated by gel-shift assays. Although treatment with LY294002, a specific inhibitor of PI3 K, decreased the phosphorylation of Akt and increased Fkhr translocation to the nucleus, these events were not sufficient to induce FasL expression and apoptosis of C6 glioma cells. Interference with Akt/Forkhead signalling by membrane-targeted Akt or removal of the FKHR-binding sites from the FasL promoter significantly abolished its activation. These results indicate that downregulation of Akt signalling and activation of Forkhead is a prerequisite for the induction of FasL promoter. It may be clinically important for pharmacological intervention in gliomas.

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Acknowledgements

We thank Drs DR Green, T Franke MJ Weber, TG Unterman for generous gifts of the plasmid constructs. This work was supported by Grants 6 P04A 017 20 (IC) and PBZ-MIN-001/P05/2002 (BK) from the State Committee for Scientific Research (Poland).

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  1. Department of Cellular Biochemistry, Laboratory of Transcription Regulation, Nencki Institute of Experimental Biology, 3 Pasteur Str., Warsaw, 02-093, Poland

    Iwona Ciechomska, Beata Pyrzynska, Piotr Kazmierczak & Bozena Kaminska

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Correspondence to Bozena Kaminska.

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Ciechomska, I., Pyrzynska, B., Kazmierczak, P. et al. Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells. Oncogene 22, 7617–7627 (2003). https://doi.org/10.1038/sj.onc.1207137

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