2. Academic Validation
  3. MEK Inhibition Induces Canonical WNT Signaling through YAP in KRAS Mutated HCT-15 Cells, and a Cancer Preventive FOXO3/FOXM1 Ratio in Combination with TNKS Inhibition

MEK Inhibition Induces Canonical WNT Signaling through YAP in KRAS Mutated HCT-15 Cells, and a Cancer Preventive FOXO3/FOXM1 Ratio in Combination with TNKS Inhibition

  • Cancers (Basel). 2019 Feb 1;11(2):164. doi: 10.3390/cancers11020164.
Nina Therese Solberg 1 2,  Maria Melheim 3 4,  Martin Frank Strand 5,  Petter Angell Olsen 6 7,  Stefan Krauss 8 9
Affiliations

Affiliations

  • 1 Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. [email protected].
  • 2 Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. [email protected].
  • 3 Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. [email protected].
  • 4 Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. [email protected].
  • 5 Department of Health Sciences, Kristiania University College, PB 1190 Sentrum, 0107 Oslo, Norway. [email protected].
  • 6 Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. [email protected].
  • 7 Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. [email protected].
  • 8 Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. [email protected].
  • 9 Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. [email protected].
PMID: 30717152 DOI: 10.3390/cancers11020164
Abstract

The majority of colorectal cancers are induced by subsequent mutations in APC and KRAS genes leading to aberrant activation of both canonical Wnt and Ras signaling. However, due to induction of feedback rescue mechanisms some cancers do not respond well to targeted inhibitor treatments. In this study we show that the APC and KRAS mutant human colorectal Cancer cell line HCT-15 induces canonical Wnt signaling through YAP in a MEK dependent mechanism. This inductive loop is disrupted with combined tankyrase (TNKS) and MEK inhibition. RNA sequencing analysis suggests that combined TNKS/MEK inhibition induces metabolic stress responses in HCT-15 cells promoting a positive FOXO3/FOXM1 ratio to reduce antioxidative and cryoprotective systems.

Keywords

FOXM1; FOXO3; MEK; RNAseq; WNT; YAP; colorectal cancer; inhibition; tankyrase.

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