Description:
<jats:title>Abstract</jats:title>
<jats:p>Background: The clinical response of locally advanced rectal cancers to preoperative chemoradiotherapy is very heterogeneous. We previously identified TCF4, the key downstream effector of the Wnt/β-catenin signaling pathway, as over-expressed in tumors that were resistant to chemoradiotherapy. The aim of this study was to explore the potential functional relevance of Wnt/ß-catenin signaling for mediating treatment resistance.</jats:p>
<jats:p>Methods: Using RNA interference, TCF4 and β-catenin were inhibited in the colorectal cancer cell lines SW837 and SW480. Subsequently, these cell lines were irradiated with varying doses of X-rays. In addition, normal retinal epithelial cells (RPE) were stimulated with Wnt-3a for 28 hours, and also irradiated. Wnt/β-catenin activity was assessed using the TOPFLASH/FOPFLASH reporter assay, and induction of Axin2 was confirmed by Western blotting.</jats:p>
<jats:p>Results: Protein levels of both TCF4 and β-catenin were considerably reduced following RNAi, accompanied by a decreased TOP/FOP reporter activity. Importantly, silencing of both proteins led to a pronounced radiosensitization in SW837 and SW480 cells. Exogenous stimulation of canonical Wnt signaling in RPE cells using Wnt-3a resulted in an increased Axin2 expression and an increased TOP/FOP reporter activity. Importantly, however, this activation of canonical Wnt signaling was associated with significant increase in resistance to radiation therapy.</jats:p>
<jats:p>Conclusion: TCF4 was found to be over-expressed in resistant rectal carcinomas, and its RNAi-mediated silencing caused a significant radiosensitization. To determine whether this effect was dependent on canonical Wnt signaling, we inhibited ß-catenin, another key factor of this pathway and binding partner of TCF4, and observed a similar sensitization to radiation therapy. Follow-up experiments show that external stimulation of canonical Wnt signaling confers radiation resistance in normal cells. These data suggest that targeting canonical Wnt signaling may represent a potential therapeutic strategy for sensitizing tumor cells to radiation. In vivo studies are ongoing to validate these results.</jats:p>
<jats:p>Citation Format: Georg Emons, Janneke Möller, Melanie Spitzner, Emil Kendziorra, Jochen Gaedcke, Margret Rave-Fränk, Tobias Pukrop, Michael Ghadimi, Thomas Ried, Marian Grade. Canonical Wnt signaling mediates resistance of colorectal cancer cells to radiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1588. doi:10.1158/1538-7445.AM2013-1588</jats:p>