Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Scholten, Donald J., Timmer, Christine M., Peacock, Jacqueline D., Pelle, Dominic W., Williams, Bart O., Steensma, Matthew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210185/
https://www.ncbi.nlm.nih.gov/pubmed/25347326
http://dx.doi.org/10.1371/journal.pone.0111431
_version_ 1782341340036595712
author Scholten, Donald J.
Timmer, Christine M.
Peacock, Jacqueline D.
Pelle, Dominic W.
Williams, Bart O.
Steensma, Matthew R.
author_facet Scholten, Donald J.
Timmer, Christine M.
Peacock, Jacqueline D.
Pelle, Dominic W.
Williams, Bart O.
Steensma, Matthew R.
author_sort Scholten, Donald J.
collection PubMed
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.
format Online
Article
Text
id pubmed-4210185
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-42101852014-10-30 Down Regulation of Wnt Signaling Mitigates Hypoxia-Induced Chemoresistance in Human Osteosarcoma Cells Scholten, Donald J. Timmer, Christine M. Peacock, Jacqueline D. Pelle, Dominic W. Williams, Bart O. Steensma, Matthew R. PLoS One Research Article 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. Public Library of Science 2014-10-27 /pmc/articles/PMC4210185/ /pubmed/25347326 http://dx.doi.org/10.1371/journal.pone.0111431 Text en © 2014 Scholten II et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Scholten, Donald J.
Timmer, Christine M.
Peacock, Jacqueline D.
Pelle, Dominic W.
Williams, Bart O.
Steensma, Matthew R.
Down Regulation of Wnt Signaling Mitigates Hypoxia-Induced Chemoresistance in Human Osteosarcoma Cells
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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210185/
https://www.ncbi.nlm.nih.gov/pubmed/25347326
http://dx.doi.org/10.1371/journal.pone.0111431
work_keys_str_mv AT scholtendonaldj downregulationofwntsignalingmitigateshypoxiainducedchemoresistanceinhumanosteosarcomacells
AT timmerchristinem downregulationofwntsignalingmitigateshypoxiainducedchemoresistanceinhumanosteosarcomacells
AT peacockjacquelined downregulationofwntsignalingmitigateshypoxiainducedchemoresistanceinhumanosteosarcomacells
AT pelledominicw downregulationofwntsignalingmitigateshypoxiainducedchemoresistanceinhumanosteosarcomacells
AT williamsbarto downregulationofwntsignalingmitigateshypoxiainducedchemoresistanceinhumanosteosarcomacells
AT steensmamatthewr downregulationofwntsignalingmitigateshypoxiainducedchemoresistanceinhumanosteosarcomacells