Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells.
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 s...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4210185?pdf=render |
| _version_ | 1819135593523707904 |
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| author | Donald J Scholten Christine M Timmer Jacqueline D Peacock Dominic W Pelle Bart O Williams Matthew R Steensma |
| author_facet | Donald J Scholten Christine M Timmer Jacqueline D Peacock Dominic W Pelle Bart O Williams Matthew R Steensma |
| author_sort | Donald J Scholten |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T10:21:33Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T10:21:33Z |
| publishDate | 2014-01-01 |
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| series | PLoS ONE |
| spelling | doaj.art-49a8beb116c24904929012ece430ecbc2022-12-21T18:29:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e11143110.1371/journal.pone.0111431Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells.Donald J ScholtenChristine M TimmerJacqueline D PeacockDominic W PelleBart O WilliamsMatthew R SteensmaOsteosarcoma (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.http://europepmc.org/articles/PMC4210185?pdf=render |
| spellingShingle | Donald J Scholten Christine M Timmer Jacqueline D Peacock Dominic W Pelle Bart O Williams Matthew R Steensma Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. PLoS ONE |
| title | Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. |
| title_full | Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. |
| title_fullStr | Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. |
| title_full_unstemmed | Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. |
| title_short | Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. |
| title_sort | down regulation of wnt signaling mitigates hypoxia induced chemoresistance in human osteosarcoma cells |
| url | http://europepmc.org/articles/PMC4210185?pdf=render |
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