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Kit signaling and negative regulation of daunorubicin-induced apoptosis: role of phospholipase Cγ

Oncogene volume 20, pages 6752–6763 (2001)Cite this article

Abstract

Previous studies have demonstrated that activation of Kit by stem cell factor (SCF), its natural ligand, or by gain-of-function point mutation in its intracellular domain, confers significant protection against apoptosis induced by growth factor deprivation or radiation. However, the effects of Kit activation on the cellular response to anti-tumor agents have not been so extensively documented. This study shows that daunorubicin-induced apoptosis and cytotoxicity were reduced in the murine Ba/F3 cells transfected with Kit (Ba/F3-Kit) in the presence of SCF and in Ba/F3 cells transfected with a constitutively active Kit variant (Ba/F3-KitΔ27), compared to either parental Ba/F3 (Ba/F3-wt) or unstimulated Ba/F3-Kit cells. In Ba/F3-wt and in Ba/F3-Kit cells, daunorubicin stimulated within 8–15 min neutral sphingomyelinase and ceramide production but not in SCF-stimulated Ba/F3-Kit or in Ba/F3-KitΔ27 whereas all Ba/F3 cells were equally sensitive to exogenous cell-permeant C6-ceramide. In Ba/F3-Kit, SCF-induced Kit activation resulted in a rapid phospholipase Cγ (PLCγ) tyrosine phosphorylation followed by diacylglycerol release and protein kinase C (PKC) stimulation. U-73122, a PLCγ inhibitor, not only blocked diacylglycerol production and PKC stimulation but also restored daunorubicin-induced sphingomyelinase stimulation, ceramide production, and apoptosis. These results suggest that Kit activation results in PLCγ-mediated PKC-dependent sphingomyelinase inhibition which contributes to drug resistance in Kit-related malignancies.

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Acknowledgements

We thank Dr T Levade, Dr A Quillet-Mary and Dr JP Jaffrézou for helpful discussion. This work was supported by l'Association pour la Recherche sur le Cancer grants 5526 (G Laurent), 5203 (M Arock), and (P Dubreuil). La Faculté de Médecine Toulouse-Rangueil (G Laurent). I Plo is a recipient of fellowship from la Ligue Nationale Contre le Cancer.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale E 9910, Institut Claudius Régaud, Toulouse, 31 052, France

    Isabelle Plo, Dominique Lautier & Guy Laurent

  2. Laboratoire de Cancérologie Expérimentale, Institut National de la Santé et de la Recherche Médicale U119, 27, bd Leï Roure, Marseille, 13009, France

    Nathalie Casteran & Patrice Dubreuil

  3. Laboratoire d'Hématologie Cellulaire et moléculaire, UPRES EA2509, Faculté de Pharmacie, Paris, 75006, France

    Michel Arock

  4. Service d'Hématologie, Centre Hospitalier Universitaire Purpan, Toulouse, 31 059, France

    Guy Laurent

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  1. Isabelle Plo
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Correspondence to Isabelle Plo.

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Plo, I., Lautier, D., Casteran, N. et al. Kit signaling and negative regulation of daunorubicin-induced apoptosis: role of phospholipase Cγ. Oncogene 20, 6752–6763 (2001). https://doi.org/10.1038/sj.onc.1204877

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