The Endosomal Protein CEMIP Links WNT Signaling to MEK1–ERK1/2 Activation in Selumetinib-Resistant Intestinal Organoids
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- Hong Quan Duong
- 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), GIGA-Molecular Biology of Diseases, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
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- Ivan Nemazanyy
- 5Paris Descartes University, Sorbonne Paris Cité, Paris, France.
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- Florian Rambow
- 6Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology and KULeuven Department of Oncology, Leuven, Belgium.
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- Seng Chuan Tang
- 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), GIGA-Molecular Biology of Diseases, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
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- Sylvain Delaunay
- 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), GIGA-Molecular Biology of Diseases, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
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- Lars Tharun
- 8Laboratory of Cancer Signaling, University of Liege, Liège, Belgium.
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- Alexandra Florin
- 8Laboratory of Cancer Signaling, University of Liege, Liège, Belgium.
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- Reinhard Büttner
- 8Laboratory of Cancer Signaling, University of Liege, Liège, Belgium.
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- Daniel Vandaele
- 9Gastroenterology Department, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
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- Pierre Close
- 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), GIGA-Molecular Biology of Diseases, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
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- Jean-Christophe Marine
- 6Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology and KULeuven Department of Oncology, Leuven, Belgium.
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- Kateryna Shostak
- 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), GIGA-Molecular Biology of Diseases, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
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- Alain Chariot
- 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), GIGA-Molecular Biology of Diseases, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
抄録
<jats:title>Abstract</jats:title> <jats:p>MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here, we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a β-catenin– and FRA-1–dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor–resistant BRAFV600E-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis. CEMIP silencing circumvented resistance to MEK1 inhibition, partly, through a decrease of both ERK1/2 signaling and c-Myc. Together, our data identify a cross-talk between Wnt and MAPK signaling cascades, which involves CEMIP. Activation of this pathway promotes survival by potentially regulating levels of specific amino acids via a Myc-associated cascade. Targeting this node may provide a promising avenue for treatment of colon cancers that have acquired resistance to targeted therapies.</jats:p> <jats:p>Significance: MEK1 inhibitor–resistant colorectal cancer relies on the scaffold and endosomal protein CEMIP to maintain ERK1/2 signaling and Myc-driven transcription. Cancer Res; 78(16); 4533–48. ©2018 AACR.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 78 (16), 4533-4548, 2018-08-14
American Association for Cancer Research (AACR)