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Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

Oncogene volume 26, pages 7038–7048 (2007)Cite this article

Abstract

Renal cell carcinoma (RCC) is resistant to chemotherapy, and this resistance is mirrored by a high apoptosis resistance of many RCC lines in vitro. Here, we report the loss of the pro-apoptotic BH3-only protein Bim in a large part of clinical RCC cases and provide evidence for a functional relevance of this loss. Immunohistochemistry of clear cell renal cell carcinoma cases and corresponding normal kidney showed strong Bim reactivity in renal tubules of all cases but loss of Bim in 35 of 45 RCC samples. Out of nine RCC cell lines investigated, six showed strongly diminished or undetectable levels of Bim protein by western blotting. Four RCC lines of varying apoptosis sensitivity were analysed further. Bcl-2, Bcl-xL, Mcl-1, Bax and Bak expression did not correlate with apoptosis sensitivity. All cell lines underwent apoptosis upon forced expression of Bax and Bim, suggesting an upstream difference. In all four lines, adriamycin induced p53 but not its targets Puma or Noxa. However, apoptosis sensitivity correlated with levels of Bim protein. Bim siRNA reduced apoptosis sensitivity in a susceptible cell line. Furthermore, inhibition of histone deacetylation restored Bim expression in cell lines. These data suggest that Bim has a function as a tumor suppressor in RCC.

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Abbreviations

CCRCC:

clear cell renal cell carcinoma

HDAC:

histone deacetylase

RCC:

renal cell carcinoma

TSA:

trichostatin A

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Acknowledgements

We thank Christina Hilpert, Antje and Anja Richter for expert technical assistance. This work was supported by the Deutsche Krebshilfe (grant 10-1923 to NZ and GH).

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Author notes

  1. S F Fischer

    Present address: 7Current address: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, Australia.,

  2. N Zantl and G Weirich: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Technical University Munich, Munich, Germany

    N Zantl

  2. Institute for Pathology, Technical University Munich, Munich, Germany

    G Weirich & C Hartmann

  3. Institute for Medical Microbiology, Technical University Munich, Munich, Germany

    H Zall, B M Seiffert, S F Fischer, S Kirschnek & G Häcker

  4. Department of Internal Medicine II, Technical University Munich, Munich, Germany

    R M Fritsch

  5. Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Berlin, Germany

    B Gillissen & P T Daniel

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Correspondence to G Häcker.

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

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Zantl, N., Weirich, G., Zall, H. et al. Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance. Oncogene 26, 7038–7048 (2007). https://doi.org/10.1038/sj.onc.1210510

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