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Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors

Oncogene volume 25, pages 722–734 (2006)Cite this article

Abstract

Rhabdoid tumors (RTs) are aggressive and currently incurable pediatric malignancies. INI1/hSNF5 is a tumor suppressor biallelically inactivated in RTs. Our previous studies have indicated that cyclin D1 is a key downstream target of INI1/hSNF5 and genesis and/or survival of RTs in vivo is critically dependent on the presence of cyclin D1. In this report, we have tested the hypothesis that therapeutic targeting of cyclin D1 is an effective means of treating RTs. We found that RNA interference of cyclin D1 in rhabdoid cells was sufficient to induce G1 arrest and apoptosis. Furthermore, we found that pharmacological intervention with low micromolar concentrations of N-(4-hydroxyphenyl)retinamide (4-HPR), which downmodulates cyclin D1, induced G1 arrest and apoptosis in rhabdoid cell lines. 4-HPR in combination with 4-hydroxy-tamoxifen (4OH-Tam), synergistically inhibited survival as well as anchorage-dependent and -independent growth of rhabdoid cells and caused synergistic induction of cell cycle arrest and apoptosis. 4-HPR and tamoxifen exhibited synergistic growth inhibition of RTs in xenograft models in vivo. The effects of combination of drugs were correlated to the depletion of cyclin D1 levels both in in vitro and in vivo tumor models. These results demonstrate that 4-HPR and tamoxifen are effective chemotherapeutic agents for RTs. We propose that downmodulation of cyclin D1 is a novel and effective therapeutic strategy for RTs.

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Acknowledgements

We thank Drs Prasad, Goldman and Birshtein at the Albert Einstein College of Medicine for critically reading the manuscript and for useful discussions. We thank Dr Beigel, University of Pennsylvania, for the kind gift of some rhabdoid cell lines and Dr Tsikitis for initial technical assistance with xenograft mice. We thank Drs M Smith and J Zweibel for kindly providing 4-HPR for animal studies. This work was supported by grants from The American Cancer Society (RSG CCG-10493) to GVK, Albert Einstein Cancer Center Pilot Project Award (CCSG # P30 CA13330) to GVK and SM, The Damon Runyon Clinical Investigator Award (CI02-12) to SM. GVK is a recipient of Irma T Hirschl Career Scientist Award and is a Mark Trauner Faculty Scholar in NeuroOncology.

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  1. Department of Molecular Genetics, Albert Einstein College of Medicine, New York, NY, USA

    D Alarcon-Vargas, Z Zhang, B Agarwal, K Challagulla, S Mani & G V Kalpana

  2. Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA

    S Mani

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  1. D Alarcon-Vargas
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  2. Z Zhang
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  3. B Agarwal
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  4. K Challagulla
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  6. G V Kalpana
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Correspondence to S Mani or G V Kalpana.

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Alarcon-Vargas, D., Zhang, Z., Agarwal, B. et al. Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors. Oncogene 25, 722–734 (2006). https://doi.org/10.1038/sj.onc.1209112

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