title: Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells.
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.
authors.affiliation: Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America; Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Scholten
authors.affiliation: Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Timmer
authors.affiliation: Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Peacock
authors.affiliation: Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America; Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Helen DeVos Childen's Hospital, Spectrum Health System, Grand Rapids, Michigan, United States of America.
authors.forename: Dominic W
authors.initials: DW
authors.lastname: Pelle
authors.affiliation: Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.affiliation: Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America; Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Helen DeVos Childen's Hospital, Spectrum Health System, Grand Rapids, Michigan, United States of America.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Steensma
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004317:Doxorubicin; D010100:Oxygen