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Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells

Oncogene volume 20, pages 7478–7485 (2001)Cite this article

Abstract

Expression of inducible heat shock protein 70 (HSP70) in tumor cells has been proposed to enhance their immunogenicity. However, HSP70 has also been demonstrated to prevent tumor cell death, a key process for the development of tumor cell immunogenicity. In the present study, we investigated the influence of the HSP70 protein level on PRO colon cancer cell growth and immunogenicity in syngeneic BDIX rats and nude mice. These cells have a basal expression of HSP70 which can be substantially increased by heat shock. When injected subcutaneously in syngeneic animals, PRO cells do not induce any detectable immune response and give rise to progressive, metastatic and lethal tumors. Stable transfection of an anti-sense hsp70 cDNA in PRO cells (PRO-70AS cells) strongly decreased HSP70 expression and sensitized cell-free extracts to cytochrome c/dATP-mediated activation of caspases. Subcutaneous injection of PRO-70AS cells induced tumors that rapidly regressed in syngeneic rats while they grew normally in nude mice. Syngeneic rats injected with PRO-70AS cells became protected against a further challenge with PRO cells. The tumor-specific immune response induced by HSP70-depleted PRO-70AS cells was associated with an increased rate of cell death in vivo. These PRO-70AS cells were also more sensitive to NO-mediated, caspase-dependent, macrophage cytotoxicity in vivo. Altogether, these results indicate that reduced level of HSP70 expression in PRO- colon cancer cells results in the generation of a specific immune response by promoting cell death in vivo.

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Acknowledgements

We thank M Martin and B Bonnotte for valuable advice and M Moutet for excellent technical assistance. Our group is supported by a special grant from the Ligue Nationale Contre le Cancer. Work supported by additional grants from the Comité de la Nièvre de la Ligue Nationale Contre le Cancer (C Garrido), Fondation contre la Leucémie and Poste Vert from INSERM (S Gurbuxani).

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Authors and Affiliations

  1. INSERM 517, IFR 100, Faculty of Medicine, Dijon, 21033, France

    Sandeep Gurbuxani, Jean-Marie Bruey, Annie Fromentin, Nicolas Larmonier, Arnaud Parcellier, François Martin, Eric Solary & Carmen Garrido

  2. Danish Cancer Society, Standboulevarden 49, DR-2100, Copenhagen, Denmark

    Marja Jäättelä

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  1. Sandeep Gurbuxani
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Correspondence to Carmen Garrido.

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Gurbuxani, S., Bruey, JM., Fromentin, A. et al. Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells. Oncogene 20, 7478–7485 (2001). https://doi.org/10.1038/sj.onc.1204948

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