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.

Autor: Solberg NT; Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. nina.therese.solberg@rr-research.no.; Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. nina.therese.solberg@rr-research.no., Melheim M; Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. maria.melheim@rr-research.no.; Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. maria.melheim@rr-research.no., Strand MF; Department of Health Sciences, Kristiania University College, PB 1190 Sentrum, 0107 Oslo, Norway. martinfrank.strand@kristiania.no., Olsen PA; Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. petter.angell.olsen@rr-research.no.; Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. petter.angell.olsen@rr-research.no., Krauss S; Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. Stefan.krauss@rr-research.no.; Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway. Stefan.krauss@rr-research.no.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2019 Feb 01; Vol. 11 (2). Date of Electronic Publication: 2019 Feb 01.
DOI: 10.3390/cancers11020164
Abstrakt: 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.
Databáze: MEDLINE
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