Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells

P. Luo, X. Yang, M. Ying, P. Chaudhry, A. Wang, H. Shimada, W. A. May, G. B. Adams, D. Mock, T. J. Triche, Q. He, L. Wu*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Although retinoic acid (RA) is a potent agent that coordinates inhibition of proliferation with differentiation of many cell types, RA-mediated signaling pathways in osteosarcoma cell differentiation are uncharacterized. In this study, we show that in human U2OS osteosarcoma cells, decreased phosphorylation of RA receptor alpha (RARα) by RA treatment or overexpressing a phosphorylation-defective mutant RARαS77A results in the inhibition of proliferation and induction of differentiation, and that U2OS cells transduced with RARαS77A suppresses tumor formation in nude mice. Moreover, using different human primary osteosarcoma cells and human mesenchymal stem cells for gene expression analysis, we found that either RA or RARαS77A induces many of the same differentiation response pathways and signaling molecules involved in U2OS cell differentiation. In addition, overexpression of the fibroblast growth factor 8f (FGF8f), one of the downstream targets induced by both RA and RARαS77A in U2OS cells, inhibits proliferation and induces expression of osteoblastic differentiation regulators. Hence, these data strongly suggest that RA-suppressed phosphorylation of RARα induces FGF8f expression to mediate differentiation response pathway in U2OS osteosarcoma cells.

Original languageEnglish (US)
Pages (from-to)2772-2783
Number of pages12
JournalOncogene
Volume29
Issue number19
DOIs
StatePublished - May 13 2010

Keywords

  • Cell-cycle G1 exit
  • Decreased CAK phosphorylation of RARα
  • RA response pathways
  • RARARα-FGF8f signaling
  • Transcriptional expression of RA target genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Luo, P., Yang, X., Ying, M., Chaudhry, P., Wang, A., Shimada, H., May, W. A., Adams, G. B., Mock, D., Triche, T. J., He, Q., & Wu, L. (2010). Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells. Oncogene, 29(19), 2772-2783. https://doi.org/10.1038/onc.2010.50