Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling
| العنوان: | Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling |
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| المؤلفون: | Georg Emons, Margret Rave-Fränk, Jochen Gaedcke, Thomas Ried, Melanie Spitzner, Yue Hu, Steven A. Johnsen, Elisabeth Heßmann, Frank Kramer, Sebastian Reineke, Noam Auslander, Hendrik A. Wolff, Janneke Möller, Tim Beissbarth, Marian Grade, B. Michael Ghadimi |
| المصدر: | Molecular Cancer Research. 15:1481-1490 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Frizzled, Beta-catenin, Cell Survival, Colorectal cancer, Radiation Tolerance, Article, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Humans, Gene silencing, RNA, Small Interfering, Wnt Signaling Pathway, Molecular Biology, beta Catenin, biology, Wnt signaling pathway, Cancer, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Disease Progression, biology.protein, Cancer research, Colorectal Neoplasms, Heterocyclic Compounds, 3-Ring, Transcription Factor 7-Like 2 Protein, TCF7L2, Chemoradiotherapy |
| الوصف: | Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy. Implications: Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481–90. ©2017 AACR. |
| تدمد: | 1557-3125 1541-7786 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8d4f52f3ab5375dfb3da46901abaa613Test https://doi.org/10.1158/1541-7786.mcr-17-0205Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8d4f52f3ab5375dfb3da46901abaa613 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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