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Ras-MAPK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis

Nachiyappan Venkatachalam1, Li Wang1, Niyumi Muthukumarana1,2,3

  • 1Department of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Cell Communication and Signaling : CCS
|May 28, 2026
PubMed
Abstract

Insights

Ras-MAPK pathway inhibitors reduce AXIN1 levels in colorectal cancer by decreasing protein synthesis. MEK1/2 inhibitors cause AXIN1 loss via global translational repression, impacting Wnt signaling in CRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • AXIN1 is a key regulator of Wnt signaling and a tumor suppressor in colorectal cancer (CRC).
  • Understanding how AXIN1 levels are controlled by pathways beyond Wnt signaling is crucial for CRC treatment.
  • AXIN1's role as a scaffold protein in the beta-catenin destruction complex highlights its importance in Wnt pathway regulation.

Purpose of the Study:

  • To investigate the regulation of AXIN1 levels by cancer pathways.
  • To determine the mechanism by which Ras-MAPK signaling affects AXIN1 protein levels.
  • To explore the therapeutic potential of targeting protein synthesis for AXIN1 regulation in CRC.

Main Methods:

  • Utilized colorectal cancer cell lines and patient-derived organoids.
  • Assessed AXIN1 levels using immunoblot, qPCR, and RNA-seq after drug treatment.
  • Employed ubiquitin-affinity immunoprecipitation, mass spectrometry, polysome, and ribosome profiling (Ribo-seq) to elucidate mechanisms.

Main Results:

  • MEK1/2 inhibitors targeting the Ras-MAPK pathway reduced AXIN1 levels in CRC models.
  • AXIN1 loss was attributed to reduced global protein synthesis via an mTOR-associated pathway, not protein degradation or transcript changes.
  • APC truncations affected basal AXIN1 levels but not the drug-induced loss dynamics.

Conclusions:

  • Ras-MAPK signaling critically controls AXIN1 protein homeostasis at the level of protein synthesis.
  • MEK1/2 inhibitors induce AXIN1 loss through global translational repression, offering a potential therapeutic strategy in CRC.
  • This study reveals a novel mechanism linking Ras-MAPK signaling to Wnt pathway regulation via translational control of AXIN1.
Keywords:
AXIN1Colorectal cancerDestruction complexMEK inhibitorRas-MAPKTranslationWntmTOR

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