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Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells

Oncogene volume 24, pages 6333–6344 (2005)Cite this article

Abstract

Kaposi's sarcoma (KS) is a common neoplasm in HIV-1-infected individuals causing significant morbidity and mortality. Despite recent advances, the pathogenesis of this potentially life-threatening neoplasm remains unclear, and there is currently no cure for KS. Notch proteins are known to play a fundamental role in cell fate decisions including proliferation, differentiation, and apoptosis. It is, therefore, not surprising that Notch proteins have been implicated in tumorigenesis and appear to function as either oncogenes or tumor suppressor proteins depending on cellular context. In this report, we demonstrate elevated levels of activated Notch-1, -2, and -4 in KS tumor cells in vivo and in vitro compared to endothelial cells, the precursor of the KS cell. Notch activation was confirmed through luciferase reporter assays and localization of Hes (Hairy/Enhancer of Split)-1 and Hey (Hairy/Enhancer of Split related with YRPW)1 (primary targets of the Notch pathway) in KS cell nuclei. Studies using γ-secretase inhibitors (GSI and LY-411,575), which block Notch activation, resulted in apoptosis in primary and immortalized KS cells. Similar studies injecting GSI into established KS cell tumors on mice demonstrated growth inhibition or tumor regression that was characterized by apoptosis in treated, but not control tumors. The results indicate that KS cells overexpress activated Notch and interruption of Notch signaling inhibits KS cell growth. Thus, targeting Notch signaling may be of therapeutic value in KS patients.

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Acknowledgements

We thank Dr Abdul Fauq for assistance with LY-411,575, Drs Gessler, Kedes, and Siodia for luciferase reporter constructs driven by the Hes-1, Hey1, and Hey2 promoters, and Dr Brian Bonish for assistance with figures. We appreciate the generosity of the AIDS and Cancer Specimen Resource, sponsored by the National Cancer Institute, in providing frozen KS tissue specimens for immunostaining. We also thank the members of the Skin Cancer Research Program at the Cardinal Bernardin Cancer Center of Loyola University for helpful discussions. This work was supported by a grant from the National Institutes of Health CA108450 (KEF) and PO1 CA59327 (BJN).

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Authors and Affiliations

  1. Department of Pathology and Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA

    Christine L Curry, Laura L Reed, Lucio Miele, Brian J Nickoloff & Kimberly E Foreman

  2. Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, IL, USA

    Christine L Curry, Brian J Nickoloff & Kimberly E Foreman

  3. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Todd E Golde

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  1. Christine L Curry
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Correspondence to Kimberly E Foreman.

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Curry, C., Reed, L., Golde, T. et al. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene 24, 6333–6344 (2005). https://doi.org/10.1038/sj.onc.1208783

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