Evidence map›Paper›PMID 42204589›Full record

ArticleCell communication and signaling : CCS2026

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

Nachiyappan Venkatachalam, Li Wang, Niyumi Muthukumarana, Robert Ihnatko, Jeroen Krijgsveld, Olga Skabkina, Antonia Leipertz, Yubin Chen, Ping Sui, Qing Zheng and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell communication and signaling : CCS, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Nachiyappan Venkatachalam *Department of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Li Wang *Department of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Niyumi MuthukumaranaDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Robert IhnatkoDivision of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jeroen KrijgsveldDivision of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Olga SkabkinaDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Antonia LeipertzDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Yubin ChenDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Ping SuiDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Qing ZhengDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Panpan TongDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Xi LiuDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Arnaud DescotDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Matthias ScheweDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Gabriele DiamanteCancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
Rene JackstadtCancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
Christoph BrochhausenDKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
Johannes BetgeDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Kim BoonekampDivision of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Michael BoutrosDivision of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Georg StoecklinDivision of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Matthias EbertDepartment of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Johanna Schott *Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Tianzuo Zhan *Department of Medicine II, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. tianzuo.zhan@medma.uni-heidelberg.de.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundAXIN1 is a central regulatory hub of many oncogenic pathways in colorectal cancer (CRC). As the main scaffold protein and least abundant component of the beta-catenin destruction complex, changes in AXIN1 levels tightly control Wnt signaling activity. How other cancer pathways beyond Wnt signaling regulate cellular AXIN1 levels is incompletely understood.

methodsColorectal cancer cell lines, murine and patient-derived intestinal and cancer organoids were used as model systems. Changes in AXIN1 levels upon drug perturbation were profiled by immunoblot, qPCR and RNA-seq. Ubiquitin-affinity immunoprecipitation assays and mass spectrometry were used to determine mechanisms of AXIN1 loss. To characterize effects on protein synthesis, we performed polysome and ribosome profiling (Ribo-seq).

resultsWe show that targeting the Ras-MAPK pathway using clinically approved MEK1/2 inhibitors induces AXIN1 loss across a panel of CRC cell lines and patient-derived organoids. In contrast to GSK3 inhibitors, MEK1/2 inhibition neither affects protein stability nor post-translational modifications of AXIN1 and only caused a minor reduction of AXIN1 transcript levels. Co-treatment with tankyrase inhibitors could partially prevent loss of AXIN1 upon MEK1/2 inhibition. Using isogenic CRC cell lines and murine intestinal organoids, we show that APC truncations strongly reduce basal cellular AXIN1 levels, but do not alter dynamics of AXIN1 loss after MEK1/2 inhibition. Polysome profiling and Ribo-seq revealed that MEK1/2 inhibitors reduce global protein synthesis via an mTOR associated pathway. This translational repression is sufficient to cause significant AXIN1 loss, as treatment with mTOR or S6K inhibitors phenocopies the effect of MEK1/2 inhibitors.

conclusionOur study demonstrates that AXIN1 protein homeostasis is critically controlled by Ras-MAPK signaling at the level of protein synthesis, and that MEK1/2 inhibitors cause AXIN1 loss by global translational repression.

Indexed as

Axin ProteinColorectal NeoplasmsProtein Biosynthesisras ProteinsTOR Serine-Threonine KinasesAnimalsCell Line, TumorHumansMiceProtein Kinase InhibitorsAXIN1 protein, humanAxin ProteinProtein Kinase Inhibitorsras ProteinsTOR Serine-Threonine KinasesAXIN1Colorectal cancerDestruction complexMEK inhibitormTORRas-MAPKTranslationWnt

Identifiers

PMID42204589
PMCPMC13217735

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.