BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.
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.
Hallahan
Andrew R
AR
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Pritchard
Joel I
JI
Chandraratna
Roshantha A S
RA
Ellenbogen
Richard G
RG
Geyer
J Russel
JR
Overland
Ryan P
RP
Strand
Andrew D
AD
Tapscott
Stephen J
SJ
Olson
James M
JM
D000818:Animals; D017209:Apoptosis; D055396:Bone Morphogenetic Protein 2; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D016212:Transforming Growth Factor beta; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D017978:Receptors, Growth Factor; D012176:Retinoids; D016212:Transforming Growth Factor beta; D052004:Bone Morphogenetic Protein Receptors