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Updated: Apr 21, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells
Donald J Scholten1, Christine M Timmer2, Jacqueline D Peacock3
1Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America; Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Abstract:
Osteosarcoma (OS) is the most common type of solid bone cancer and remains the second leading cause of cancer-related death for children and young adults. Hypoxia is an element intrinsic to most solid-tumor microenvironments, including that of OS, and is associated with resistance to therapy, poor survival, and a malignant phenotype. Cells respond to hypoxia through alterations in gene expression, mediated most notably through the hypoxia-inducible factor (HIF) class of transcription factors. Here we investigate hypoxia-induced changes in the Wnt/β-catenin signaling pathway, a key signaling cascade involved in OS pathogenesis. We show that hypoxia results in increased expression and signaling activation of HIF proteins in human osteosarcoma cells. Wnt/β-catenin signaling is down-regulated by hypoxia in human OS cells, as demonstrated by decreased active β-catenin protein levels and axin2 mRNA expression (p<0.05). This down-regulation appears to rely on both HIF-independent and HIF-dependent mechanisms, with HIF-1α standing out as an important regulator. Finally, we show that hypoxia results in resistance of human OS cells to doxorubicin-mediated toxicity (6-13 fold increase, p<0.01). These hypoxic OS cells can be sensitized to doxorubicin treatment by further inhibition of the Wnt/β-catenin signaling pathway (p<0.05). These data support the conclusion that Wnt/β-catenin signaling is down-regulated in human OS cells under hypoxia and that this signaling alteration may represent a viable target to combat chemoresistant OS subpopulations in a hypoxic niche.
Insights
Hypoxia in osteosarcoma (OS) down-regulates Wnt/β-catenin signaling, increasing chemoresistance. Inhibiting this pathway can re-sensitize OS cells to doxorubicin, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Osteosarcoma (OS) is a common bone cancer with poor survival rates, particularly in children and young adults.
- Tumor hypoxia is linked to therapy resistance, malignancy, and poor prognosis in OS.
- Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, impacting cancer progression.
Purpose of the Study:
- To investigate the impact of hypoxia on the Wnt/β-catenin signaling pathway in human osteosarcoma cells.
- To determine the role of HIF proteins in hypoxia-induced Wnt/β-catenin pathway alterations.
- To explore the therapeutic potential of targeting Wnt/β-catenin signaling in chemoresistant hypoxic OS.
Main Methods:
- Cultured human osteosarcoma cells under normoxic and hypoxic conditions.
- Assessed HIF protein expression and activation.
- Measured Wnt/β-catenin pathway activity via active β-catenin and axin2 mRNA levels.
- Evaluated doxorubicin sensitivity and the effect of Wnt/β-catenin inhibition on chemoresistance.
Main Results:
- Hypoxia increased HIF protein expression and signaling in OS cells.
- Wnt/β-catenin signaling was significantly down-regulated by hypoxia, involving HIF-dependent and independent mechanisms.
- Hypoxic OS cells exhibited 6-13 fold resistance to doxorubicin.
- Inhibiting Wnt/β-catenin signaling sensitized hypoxic OS cells to doxorubicin.
Conclusions:
- Hypoxia down-regulates Wnt/β-catenin signaling in human osteosarcoma.
- HIF-1α is a key regulator in this hypoxia-induced pathway modulation.
- Targeting Wnt/β-catenin signaling offers a promising strategy to overcome doxorubicin resistance in hypoxic osteosarcoma.
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