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Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

Oncogene volume 26, pages 6653–6664 (2007)Cite this article

Abstract

Oncostatin M (OSM), a cytokine of the interleukin-6 family, induces growth arrest and differentiation of osteoblastic cells into glial-like/osteocytic cells. Here, we asked whether OSM regulates apoptosis of normal or transformed (osteosarcoma) osteoblasts. We show that OSM sensitizes cells to apoptosis induced by various death inducers such as staurosporine, ultraviolet or tumor necrosis factor-α. Apoptosis is mediated by the mitochondrial pathway, with release of cytochrome c from the mitochondria to the cytosol and activation of caspases-9 and -3. DNA micro-arrays revealed that OSM modulates the expression of Bax, Bad, Bnip3, Bcl-2 and Mcl-1. Pharmacological inhibitors, dominant-negative signal transducer and activator of transcriptions (STATs), stable RNA interference and knockout cells indicated that the transcription factors p53 and STAT5, which are activated by OSM, are implicated in the sensitization to apoptosis, being responsible for Bax induction and Bcl-2 reduction, respectively. These results indicate that, in addition to growth arrest and induced differentiation, OSM also sensitizes normal and transformed osteoblasts to apoptosis by a mechanism implicating (i) activation and nuclear translocation of STAT5 and p53 and (ii) an increased Bax/Bcl-2 ratio. Therefore, association of OSM with kinase inhibitors such as Sts represents new therapeutic opportunities for wild-type p53 osteosarcoma.

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Acknowledgements

We thank Isabelle Guisle-Marsollier (Inserm U533, Nantes, France) for her help on micro-arrays, and Caroline Colombeix (IFR26, Nantes, France) for the Confocal Microscopy. This work was supported by Inserm, the Ministère de la Recherche and La Ligue Contre le Cancer. CC is a recipient from of fellowship from the Région Pays de la loire.

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Authors and Affiliations

  1. INSERM, ERI 7, Nantes, France

    C Chipoy, B Brounais, V Trichet, S Battaglia, M Berreur, F Rédini, D Heymann & F Blanchard

  2. Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, EA3822, Nantes, France,

    C Chipoy, B Brounais, V Trichet, S Battaglia, M Berreur, F Rédini, D Heymann & F Blanchard

  3. INSERM, U601, Nantes, France

    L Oliver & P Juin

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  1. C Chipoy
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Correspondence to C Chipoy or F Blanchard.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Chipoy, C., Brounais, B., Trichet, V. et al. Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53. Oncogene 26, 6653–6664 (2007). https://doi.org/10.1038/sj.onc.1210492

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