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Heat shock cognate 70 protein secretion as a new growth arrest signal for cancer cells

Oncogene volume 29, pages 117–127 (2010)Cite this article

Abstract

Earlier studies indicated that density-arrested cancer cells released an unidentified growth inhibitor whose secretion was prevented by overexpression of the lysosomal protease cathepsin D (cath D). In this study, this growth inhibitor was purified by affinity chromatography and identified as the heat shock cognate 70 protein (hsc70) based on its peptide microsequencing and specific antibody recognition. Among intracellular proteins, including other heat shock proteins, only constitutive hsc70 was secreted in response to the high-cell density. Moreover, hsc70 secretion from cancer cells was generated by serum deprivation, whereas its cellular concentration did not change. Prevention of Hsc70 secretion by cath D overexpression was associated with the formation of multilayer cell cultures, thus indicating a loss of contact inhibition. In addition, we showed that supplementing the culture medium with purified hsc70 inhibited cell proliferation in the nanomolar range. Conversely, removal of this extracellular hsc70 from the medium by either retention on ADP-agarose or competition at the Hsc70 binding site restored cell proliferation. Hsc70 appears active in human breast cancer cells and hypersecreted by direct cath D inhibition. These results suggest a new role of this secreted hsc70 chaperone in cell proliferation that might account for the higher tumor growth of cancer cells overexpressing cath D.

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Acknowledgements

We thank Jean Derancourt, (Centre de Recherches de Biochimie Macromoleculaire du CNRS, 1919 Route de Mende, 34293 Montpellier Cedex 5, France) for peptide fragments analysis. The authors thank the Centre Régional d’Imagerie Cellulaire (Montpellier—France) for access to the scanning microscopy facilities. This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur le Cancer, the Ligue contre le cancer, Comité de l’Hérault (fellowship to MM), and CNRS.

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Authors and Affiliations

  1. IRCM, institut de Recherche en Cancérologie de Montpellier, Montpellier, France

    P Nirdé, D Derocq, M Maynadier, M Chambon, I Basile, M Gary-Bobo & M Garcia

  2. INSERM, Unité 896, Montpellier, France

    P Nirdé, D Derocq, M Maynadier, M Chambon, I Basile, M Gary-Bobo & M Garcia

  3. Université Montpellier1, Montpellier, France

    P Nirdé, D Derocq, M Maynadier, M Chambon, I Basile, M Gary-Bobo & M Garcia

  4. CRLC Val d’Aurelle Paul Lamarque, Montpellier, France

    P Nirdé, D Derocq, M Maynadier, M Chambon, I Basile, M Gary-Bobo & M Garcia

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  1. P Nirdé
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Correspondence to M Garcia.

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Nirdé, P., Derocq, D., Maynadier, M. et al. Heat shock cognate 70 protein secretion as a new growth arrest signal for cancer cells. Oncogene 29, 117–127 (2010). https://doi.org/10.1038/onc.2009.311

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