Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/β-catenin signaling

Georg Emons, Melanie Spitzner, Sebastian Reineke, Janneke Möller, Noam Auslander, Frank Kramer, Yue Hu, Tim Beissbarth, Hendrik A. Wolff, Margret Rave-Fränk, Elisabeth Heßmann, Jochen Gaedcke, B. Michael Ghadimi, Steven Johnsen, Thomas Ried, Marian Grade

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1481-1490
Number of pages10
JournalMolecular Cancer Research
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

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Catenins
Chemoradiotherapy
Colorectal Neoplasms
Radiation
Rectal Neoplasms
Wnt Proteins
Frizzled Receptors
Peroxisome Proliferator-Activated Receptors
Gene Expression Profiling
Metabolic Networks and Pathways
Small Interfering RNA
Transcription Factors
Ligands
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Emons, G., Spitzner, M., Reineke, S., Möller, J., Auslander, N., Kramer, F., ... Grade, M. (2017). Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/β-catenin signaling. Molecular Cancer Research, 15(11), 1481-1490. https://doi.org/10.1158/1541-7786.MCR-17-0205

Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/β-catenin signaling. / Emons, Georg; Spitzner, Melanie; Reineke, Sebastian; Möller, Janneke; Auslander, Noam; Kramer, Frank; Hu, Yue; Beissbarth, Tim; Wolff, Hendrik A.; Rave-Fränk, Margret; Heßmann, Elisabeth; Gaedcke, Jochen; Ghadimi, B. Michael; Johnsen, Steven; Ried, Thomas; Grade, Marian.

In: Molecular Cancer Research, Vol. 15, No. 11, 01.11.2017, p. 1481-1490.

Research output: Contribution to journalArticle

Emons, G, Spitzner, M, Reineke, S, Möller, J, Auslander, N, Kramer, F, Hu, Y, Beissbarth, T, Wolff, HA, Rave-Fränk, M, Heßmann, E, Gaedcke, J, Ghadimi, BM, Johnsen, S, Ried, T & Grade, M 2017, 'Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/β-catenin signaling', Molecular Cancer Research, vol. 15, no. 11, pp. 1481-1490. https://doi.org/10.1158/1541-7786.MCR-17-0205
Emons, Georg ; Spitzner, Melanie ; Reineke, Sebastian ; Möller, Janneke ; Auslander, Noam ; Kramer, Frank ; Hu, Yue ; Beissbarth, Tim ; Wolff, Hendrik A. ; Rave-Fränk, Margret ; Heßmann, Elisabeth ; Gaedcke, Jochen ; Ghadimi, B. Michael ; Johnsen, Steven ; Ried, Thomas ; Grade, Marian. / Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/β-catenin signaling. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 11. pp. 1481-1490.
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abstract = "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.",
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AU - Auslander, Noam

AU - Kramer, Frank

AU - Hu, Yue

AU - Beissbarth, Tim

AU - Wolff, Hendrik A.

AU - Rave-Fränk, Margret

AU - Heßmann, Elisabeth

AU - Gaedcke, Jochen

AU - Ghadimi, B. Michael

AU - Johnsen, Steven

AU - Ried, Thomas

AU - Grade, Marian

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