Targeted inhibition of T-cell factor activity promotes syndecan-2 expression and sensitization to doxorubicin in osteosarcoma cells and bone tumors in mice.

Abstract

Alterations of Wnt signaling appear to be involved in the pathogenesis of osteosarcoma, presenting mutations of adenomatous polyposis coli (APC) and epigenetic downregulation of Wnt inhibitory factor 1. However, the precise role of Wnt effectors in the bone cancer progression remains unclear. We previously showed that Wnt/β-catenin/T-cell factor (TCF) activation are responsible for the repression of syndecan-2, a key modulator of apoptosis and chemosensitivity in osteosarcoma cells, suggesting a role of Wnt signaling in chemoresistance. In this study, we investigated the functional relationship between syndecan-2, Wnt/β-catenin/TCF signaling and chemosensitivity in these cells. To this goal, we selected resistant osteosarcoma cells from sensitive human cell lines using repeated exposures to doxorubicin. In doxorubicin-responsive but not in doxorubicin-resistant-derived cells syndecan-2 expression was upregulated by doxorubicin treatment. Moreover, syndecan-2 overexpression restored the sensitivity to doxorubicin in resistant-derived cells. We found that syndecan-2 induction by doxorubicin is forkhead box protein O3A (Foxo3a)-dependent. Foxo3a overexpression resulted in increased syndecan-2 expression in sensitive and resistant-derived cells. Doxorubicin modulated Foxo3a binding on syndecan-2 gene promoter and induced Foxo-dependent inhibition of Wnt/TCF activity. Conversely, β-catenin/TCF activation impaired syndecan-2 induction by doxorubicin, indicating that Wnt signaling is competing with the action of the cytotoxic drug. However, β-catenin was also found to be required for Foxo3a activity. Consistently, Dickkopf 1 (DKK1) and secreted frizzled-related protein 1 (sFRP-1) altered doxorubicin action in sensitive cells, whereas inhibition of TCF activity strongly decreased cell viability and increased sensitivity to doxorubicin in sensitive and resistant cells. TCF inhibition also increased the effect of doxorubicin treatment in an orthotopic bone tumor model in mice. Altogether, these data provide evidence that the repression of syndecan-2 by Wnt/β-catenin/TCF signaling contributes to the resistance of osteosarcoma cells to doxorubicin and suggest that TCF inhibition may represent a novel therapeutic strategy in osteosarcoma.

• Authors: François-Xavier Dieudonné, Allison Marion, Pierre J Marie, Dominique Modrowski
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 27 Issue 10 Pg. 2118-29 (Oct 2012) ISSN: 1523-4681 [Electronic] United States
• PMID: 22550000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Bone and Mineral Research.

Chemical References

• DKK1 protein, human
• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• Intracellular Signaling Peptides and Proteins
• TCF Transcription Factors
• WD repeat containing planar cell polarity effector
• Syndecan-2
• Doxorubicin

Topics

• Animals
• Apoptosis (drug effects)
• Bone Neoplasms (drug therapy, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Gene Targeting
• Glycoproteins (metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Intracellular Signaling Peptides and Proteins
• Male
• Mice
• Mice, Inbred BALB C
• Osteosarcoma (drug therapy, pathology)
• Syndecan-2 (metabolism)
• TCF Transcription Factors (genetics, metabolism)
• Transcription, Genetic (drug effects)
• Wnt Signaling Pathway (drug effects)