BMP-2 Mediates Retinoid-Induced Apoptosis in Medulloblastoma Cells Through a Paracrine Effect

Nat Med. 2003 Aug;9(8):1033-8. doi: 10.1038/nm904. Epub 2003 Jul 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein Receptors
  • Bone Morphogenetic Proteins / metabolism*
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Female
  • Gene Expression Profiling
  • Humans
  • Medulloblastoma / metabolism*
  • Medulloblastoma / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Paracrine Communication*
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism
  • Retinoids / pharmacology*
  • Transforming Growth Factor beta*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • BMP2 protein, human
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Receptors, Growth Factor
  • Retinoids
  • Transforming Growth Factor beta
  • Bone Morphogenetic Protein Receptors