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SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

Oncogene volume 30, pages 4887–4900 (2011)Cite this article

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Abstract

Aberrant expression of Secreted Protein Acidic and Rich in Cysteine (SPARC)/osteonectin has been associated with an invasive tumor cell phenotype and poor outcome in human melanomas. Although it is known that SPARC controls melanoma tumorigenesis, the precise role of SPARC in melanoma cell survival is still unclear. Here, we show that SPARC has a cell-autonomous survival activity, which requires Akt-dependent regulation of p53. Suppression of SPARC by RNA interference in several human melanoma cells and xenografted A375 tumors triggers apoptotic cell death through the mitochondrial intrinsic pathway and activation of caspase-3. Cell death induced by depletion of SPARC is dependent on p53 and induction of Bax, and results in the generation of ROS. Stabilization of p53 in SPARC-depleted cells is associated with a decrease in Akt-mediated activating phosphorylation of MDM2. Inhibition of Akt signaling pathway is important for the observed changes as overexpression of constitutively active Akt protects cells against apoptosis induced by SPARC depletion. Conversely, increased expression of SPARC stimulates Akt and MDM2 phosphorylation, thus facilitating p53 degradation. Finally, we show that overexpression of SPARC renders cells more resistant to the p53-mediated cytotoxic effects of the DNA-damaging drug actinomycin-D. Our study indicates that SPARC functions through activation of Akt and MDM2 to limit p53 levels and that acquired expression of SPARC during melanoma development would confer survival advantages through suppression of p53-dependent apoptotic pathways.

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Acknowledgements

This work was supported in part by INSERM (Institut National de la Santé et de la Recherche Médicale) and grant 1136 from ARC (Association pour la Recherche sur le Cancer). S Tartare-Deckert is a recipient of a Contrat d'Interface Clinique, Service de Dermatologie, CHU de Nice.

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Authors and Affiliations

  1. INSERM, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Biology and Pathologies of Melanocytes, Nice, France

    N Fenouille, M Tichet, G Zimniak, P Abbe, S Rocchi, J-P Ortonne, R Ballotti & S Tartare-Deckert

  2. University of Nice—Sophia Antipolis, Faculté de médecine, Institut Signalisation et Pathologie (IFR50), Nice, France

    N Fenouille, A Puissant, M Tichet, G Zimniak, P Abbe, A Mallavialle, S Rocchi, J-P Ortonne, M Deckert, R Ballotti & S Tartare-Deckert

  3. INSERM, U895, C3M, Cell Death Differentiation and Cancer, Nice, France

    A Puissant

  4. INSERM, U576, Nice, France

    A Mallavialle & M Deckert

  5. Department of Dermatology, Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Archet, Nice, France

    S Rocchi, R Ballotti & S Tartare-Deckert

  6. Department of Clinical Hematology, CHU de Nice, Hôpital Archet, Nice, France

    M Deckert

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Correspondence to S Tartare-Deckert.

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Fenouille, N., Puissant, A., Tichet, M. et al. SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival. Oncogene 30, 4887–4900 (2011). https://doi.org/10.1038/onc.2011.198

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