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BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect

Nature Medicine volume 9, pages 1033–1038 (2003)Cite this article

Abstract

The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.

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Figure 1: Retinoid activity in primary tumors and D283 xenografts.
Figure 2: Retinoid-induced apoptosis and neurogenesis in medulloblastoma cell lines.
Figure 3: RAR agonist-induced changes in gene expression.
Figure 4: BMP-2 activity on medulloblastoma cells.

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Acknowledgements

We appreciate tissue procurement assistance from M. Bobola and M. Gross, neuropathology assistance from K. Patterson, statistical advice from M. LeBlanc and C. Kooperberg, and administrative assistance from S. Heiner and J. Stoeck. The microarray analyses were performed in the FHCRC DNA Array Shared Resource, which is directed by J. Delrow and supported by a grant from the W. Keck Foundation. This work was supported by an Emily Dorfman Foundation Fellowship (A.H.), an Immunex fellowship for interdisciplinary studies (A.H.), a Burroughs Wellcome Fund Career Award and Damon Runyon-Lilly Clinical Investigator Award (J.M.O.), and the Children's Hospital Seattle Brain Tumor Research Endowment.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Andrew R Hallahan, Joel I Pritchard, Ryan P Overland, Andrew D Strand & James M Olson

  2. Division of Pediatric Oncology, University of Washington/Children's Hospital, Seattle, 98105, Washington, USA

    Andrew R Hallahan, J Russel Geyer & James M Olson

  3. Retinoid Research, Allergan Incorporated, Irvine, 92623, California, USA

    Roshantha A S Chandraratna

  4. Department of Neurosurgery, University of Washington/Children's Hospital, Seattle, 98105, Washington, USA

    Richard G Ellenbogen

  5. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Stephen J Tapscott

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Correspondence to James M Olson.

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R.A.S.C. is employed by Allergan, which provided a subset of the compounds used to elucidate the mechanism of retinoid-induced apoptosis.

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Hallahan, A., Pritchard, J., Chandraratna, R. et al. BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med 9, 1033–1038 (2003). https://doi.org/10.1038/nm904

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