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

Oncogene volume 29, pages 2772–2783 (2010)Cite this article

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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.

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Acknowledgements

This study was supported by Grants from the National Institutes of Health R21 CA111440 and R01 CA120512 to L Wu, and 1 UO1 CA114757-01 to TJ Triche.

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Author notes

  1. P Luo and X Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Childrens Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA

    P Luo, X Yang, M Ying, P Chaudhry, A Wang, H Shimada, D Mock, T J Triche & L Wu

  2. University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    H Shimada, W A May, G B Adams, T J Triche & L Wu

  3. Department of Pediatrics, Childrens Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA

    W A May

  4. Center for Stem Cell and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    G B Adams

  5. Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China

    Q He

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Correspondence to L Wu.

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Luo, P., Yang, X., Ying, M. et al. Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells. Oncogene 29, 2772–2783 (2010). https://doi.org/10.1038/onc.2010.50

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