Wnt signaling controls radiosensitivity via cyclooxygenase‐2‐mediated Ku expression in head and neck cancer

Abstract

It has been proposed that Wnt signaling pathway may be a key radioprotective mechanism in irradiated cancer cells; however, the specific radioresistance mechanisms remain not to be fully clarified. Here we elucidate a novel signaling pathway of radioresistance in head and neck cancer (HNC) cell lines involving interactions among the Wnt signaling pathway, cyclooxygenase-2 (COX-2) and Ku expression. Activation of the Wnt signaling pathway by (2 0 Z,3 0 E)-6-bromoindirubin-3 0 -oxime (BIO) resulted in bcatenin cytoplasmic accumulation and translocation to the nucleus, upregulated Ku expression and increased radioresistance in the COX-2-expressing HNC cell line. In contrast, Wnt singaling activation by BIO had no effects on Ku expression and radiosensitivity in a HNC cell line negative for COX-2. Interactions between Wnt singaling and Ku were indirectly regulated by COX-2. Blockage of COX-2 signaling led to the suppression of b-catenin-induced Ku expression, and to consequent recovery of the radiosensitivity in HNC cells. Our results conclusively suggest that b-catenin plays a pivotal role in the regulation of Ku expression via the proposed COX-2 intracellular pathway, thus supporting a novel radioresistance mechanism of HNC. ' 2007 Wiley-Liss, Inc.

β-Catenin Is a Mediator of the Response of Fibroblasts to Irradiation

“…17 This effect is also demonstrated in vivo, in which irradiation causes a drastic loss of ␤-catenin staining in the gastrointestinal epithelium. 41 In contrast to these studies, we found an increase in ␤-catenin protein abundance and transcriptional activity after irradiation in both mouse and human fibroblast cell cultures, as well as during wound healing in vivo.…”

“…The notion that ␤-catenin promotes cell survival after irradiation is supported by studies showing that Wnt ligands promote survival in other cell types after irradiation, for instance in head and neck cancers and in mammary progenitor cells. 15,17 These data suggest that the difference in regulation of ␤-catenin in response to irradiation between different cell types could in part be responsible for variability in the response to irradiation. Because ␤-catenin acts to increase proliferation rate and maintain cell viability, its activation by irradiation in fibroblasts likely acts to make this cell type relatively resistant to irradiation.…”

“…[13][14][15] In epithelial cells, activation of ␤-catenin-mediated signaling usually results in improved cell survival after irradiation. 13,[15][16][17] Because canonical Wnt signaling is activated in fibrotic processes and plays a crucial role in normal wound repair, it is possible that ␤-catenin signaling is a key component mediating the effect of irradiation on fibroblast dysregulation. Therefore, in this study we tested the hypothesis that ␤-catenin partially mediates the response of fibroblasts to ionizing radiation.…”

Activation of Wnt/β-catenin signalling pathway induces chemoresistance to interferon-α/5-fluorouracil combination therapy for hepatocellular carcinoma

“…Analysis of the molecular and signalling mechanism of resistance of cancer stem/progenitor cells should be important for the development of new therapeutic strategies. Recent studies showed that the Wnt/b-catenin pathway plays a role in radiation and/or chemotherapy resistance of various malignancies such as leukaemia, head and neck tumours, prostate cancer and HCC (Jamieson et al, 2004;Ohigashi et al, 2005;Chang et al, 2008;Yang et al, 2008). In this study, we also showed that activation of Wnt/b-catenin signalling by a specific GSK-3 inhibitor in hepatoma cell lines decreased the susceptibility to IFN-a/5-FU through a reduction in their DNA synthesis inhibitory effects and regulation of cell cycle progression.…”

Epithelial-mesenchymal axis in head and neck cancer cell lines

“…[12] The molecular and macromolecular changes that underlie loss of epithelial cell-cell adhesion, loss of apical-basal polarity and loss of epithelial anchorage to the basement membrane have been described for numerous cancers including those of the head and neck. [13] Known EMT biomarkers in HNSCC include cell surface proteins (E-cadherin, N-cadherin), [14][15][16] cytoskeleton proteins (β-catenin, Vimentin), [14,17,18] extracellular matrix proteins (Fibronectin) [19,20] and transcription factors (Snail1). [21,22] The process of EMT has been associated with the gain of stem cell-like properties, [23] with numerous cancer stem cell markers described for head and neck cancers including: CD133, CD44, CD24, ALDH1, ABCG2 and Bmi1.…”