Nature Medicine9, 1033 - 1038 (2003)
Published online: 20 July 2003; | doi:10.1038/nm904
BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect
Andrew R Hallahan1, 2, Joel I Pritchard1, Roshantha A S Chandraratna3, Richard G Ellenbogen4, J Russel Geyer2, Ryan P Overland1, Andrew D Strand1, Stephen J Tapscott5
& James M Olson1, 2
1
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
2
Division of Pediatric Oncology, University of Washington/Children's Hospital, Seattle, Washington 98105, USA.
3
Retinoid Research, Allergan Incorporated, Irvine, California 92623, USA.
4
Department of Neurosurgery, University of Washington/Children's Hospital, Seattle, Washington 98105, USA.
5
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Correspondence should be addressed to James M Olson jolson@fhcrc.org
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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