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GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-meditated killing

Oncogene volume 25, pages 1496–1508 (2006)Cite this article

Abstract

The resistance of tumours to immune-mediated lysis has been linked to the biology of matrix metalloproteinases (MMPs), and specifically to the cell surface expression of MMPs by the tumour cell. The endogenous tissue inhibitors of metalloproteinases (TIMPs) exhibit diverse physiological/biological functions including the moderation of tumour growth, metastasis and apoptosis. These biologic activities are mediated in part by the stoichiometry of TIMP/MMP/cell surface protein interactions. A glycosylphosphatidylinositol (GPI) anchor was fused to TIMP-1 to focus defined concentrations of this inhibitory protein on the surface of three renal cell carcinoma (RCC) cell lines (RCC-26, RCC-53 and A498) independently of cell surface protein–protein interactions. Exogenously added TIMP-1-GPI efficiently inserted into the RCC cell membrane and dramatically altered the association of MMPs with the cell surface. TIMP-1-GPI treatment inhibited RCC proliferation and rendered the normally FAS-resistant RCC cells sensitive to FAS-induced apoptosis but did not alter perforin-mediated lysis by cytotoxic effector cells. The increased sensitivity to FAS-mediated apoptosis correlated with an alteration in the balance of pro- and antiapoptotic BCL-2-family proteins. By interfering with the proliferative capacity and inducing sensitivity to immune effector mechanisms GPI-anchored TIMP-1 may represent a more effective version of the TIMP-1 protein for therapeutic strategies.

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Acknowledgements

This work was supported by SFB 571 (C2), GRK438, a MUCOS-Stifung and DFG grant (NE 648/2-1) to PJN. SFB455 supported EN and DJS (Projects C5 and C1, respectively) and Madleine Schickedanz KinderKrebsstiftung and MUCOS-Stifung support was given to IvL.

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Authors and Affiliations

  1. Medizinische Poliklinik, Ludwig-Maximilians-University of Munich, Munich, Germany

    R Djafarzadeh, M Notohamiprodjo, I von Luettichau & P J Nelson

  2. GSF-Institute of Molecular Immunology, Munich, Germany

    E Noessner & D J Schendel

  3. Institute for Immunology, Ludwig-Maximilians-University, Munich, Germany

    H Engelmann

  4. Childrens Hospital Medical Center, University of Technology, Munich, Germany

    I von Luettichau

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  1. R Djafarzadeh
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  2. E Noessner
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  3. H Engelmann
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  4. D J Schendel
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  6. I von Luettichau
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  7. P J Nelson
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Correspondence to P J Nelson.

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Djafarzadeh, R., Noessner, E., Engelmann, H. et al. GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-meditated killing. Oncogene 25, 1496–1508 (2006). https://doi.org/10.1038/sj.onc.1209188

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