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.

Wnt agonist stimulates liver regeneration after small‐for‐size liver transplantation in rats

“…The mechanisms of attenuated β‐catenin activation are unclear. Significant oxidant stress and markedly increased free radical production in SFSG may be one reason, as many studies have shown that hypoxia or I/R injury could downregulate Wnt/β‐catenin signaling . However, Funato et al.…”

“…Significant oxidant stress and markedly increased free radical production in SFSG 32,40,41 may be one reason, as many studies have shown that hypoxia or I/R injury could downregulate Wnt/β-catenin signaling. 19,35,42,43 However, Funato et al showed that treatment of cells with a low dose of reactive oxygen species (ROS) induces rapid stabilization of β-catenin and a concomitant increase in the expression of endogenous Wnt target genes. 44 Therefore, we speculate that the different levels of ROS in SFSG and half-size grafts may be the reason that there is attenuated β-catenin activation in SFSG, but not in half-size liver grafts.…”

Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

“…In another study, Scholten II et al reported that Wnt/βcatenin signaling is downregulated by hypoxia in osteosarcoma cells (OS), which appears to rely on both HIF-independent and -dependent mechanisms. 81 This study suggested that an inverse association between Wnt/βcatenin and HIF, but interestingly further downregulation of Wnt/βcatenin, mitigated the hypoxia-induced chemoresistance in these cells. 81 Santoyo-Ramos et al suggested even complicated interaction between Wnt/βcatenin and HIF-1.…”

“…81 This study suggested that an inverse association between Wnt/βcatenin and HIF, but interestingly further downregulation of Wnt/βcatenin, mitigated the hypoxia-induced chemoresistance in these cells. 81 Santoyo-Ramos et al suggested even complicated interaction between Wnt/βcatenin and HIF-1. 82 PIn hypoxic colon cancer cells, HIF-1α promoted Wnt/βcatenin signaling, EMT, and stemness, while HIF-2α seems to negatively regulate Wnt/βcatenin signaling.…”

Inhibition of WNT/β-catenin signaling under serum starvation and hypoxia induces adipocytic transdifferentiation in human leiomyoma cells

“…Moreover, serum deprivation has been shown to result in the downregulation of the WNT/β-catenin signaling in cancer cells by upregulated Wnt3a leading to the internalization of low-density lipoprotein receptor-related protein 6, which reduces the nuclear accumulation of βcatenin [22]. The hypoxia-induced downregulation of βcatenin has been also described in human cancer cells [23,24]. Thus, serum starvation and hypoxia might have functioned cooperatively in the further inhibition of WNT/βcatenin signaling, leading to the alteration in the differentiation of the current XAV939-treated leiomyoma cells.…”