Related Experiment Video

Updated: Jan 29, 2026

Modeling Paracrine Noncanonical Wnt Signaling In Vitro
11:14

Modeling Paracrine Noncanonical Wnt Signaling In Vitro

Published on: December 10, 2021

1.9K

MEK Inhibition Induces Canonical WNT Signaling through YAP in KRAS Mutated HCT-15 Cells, and a Cancer Preventive

Nina Therese Solberg1,2, Maria Melheim3,4, Martin Frank Strand5

  • 1Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway. nina.therese.solberg@rr-research.no.

Cancers
|February 6, 2019
PubMed

Insights

Targeted therapy for colorectal cancer (CRC) can fail due to feedback mechanisms. This study reveals that inhibiting tankyrase (TNKS) and MEK simultaneously disrupts WNT signaling in CRC cells, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Colorectal cancer (CRC) often involves mutations in APC and KRAS genes, activating WNT and RAS pathways.
  • Feedback mechanisms can lead to resistance against targeted therapies in some cancers.

Purpose of the Study:

  • To investigate the mechanism of canonical WNT signaling induction in APC/KRAS mutant HCT-15 colorectal cancer cells.
  • To evaluate the efficacy of combined tankyrase (TNKS) and MEK inhibition in disrupting this signaling loop.

Main Methods:

  • Utilized the HCT-15 colorectal cancer cell line with APC and KRAS mutations.
  • Employed combined tankyrase (TNKS) and MEK inhibition.
  • Performed RNA sequencing analysis to assess cellular responses.

Main Results:

  • Demonstrated that HCT-15 cells induce canonical WNT signaling via YAP in a MEK-dependent manner.
  • Showed that combined TNKS and MEK inhibition effectively disrupts this inductive loop.
  • RNA sequencing revealed that combined inhibition triggers metabolic stress and alters the FOXO3/FOXM1 ratio, reducing antioxidative systems.

Conclusions:

  • Combined TNKS and MEK inhibition is a promising strategy to overcome resistance in APC/KRAS mutant colorectal cancers.
  • This approach disrupts a key signaling axis and induces metabolic vulnerability.
  • Further research into metabolic reprogramming and antioxidative pathways is warranted for CRC treatment development.
Keywords:
FOXM1FOXO3MEKRNAseqWNTYAPcolorectal cancerinhibitiontankyrase

More Related Videos

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

10.6K
A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells10:13

A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells

Published on: July 3, 2013

11.6K

Related Concept Videos

Non-Canonical Wnt Signaling Pathways01:41

Non-Canonical Wnt Signaling Pathways

Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
8.4K
Canonical Wnt Signaling Pathway02:54

Canonical Wnt Signaling Pathway

The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
10.6K
Feedback Inhibition00:46

Feedback Inhibition

Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.1K
Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
92.2K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
6.0K
Cancer Prevention02:59

Cancer Prevention

Several factors can increase the risk of cancer in an individual. About 50% of cancer cases can be prevented by adopting a healthy lifestyle, regular exercise, eating healthy, and following a modest cancer prevention diet. Epidemiological studies have consistently shown that populations with vegetable and fruit-rich diets have reduced the incidence of cancer. On the other hand, populations who have a diet rich in animal fat, red meat, junk food, or high calories are predisposed to cancer.
Some...
8.1K