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

ABSTRACT: In this study, we deciphered cellular mechanisms underlying AXIN1 loss by MEK1/2 inhibition in colorectal cancer (CRC). We observed that both MEK1/2 and GSK3B inhibitors strongly reduce AXIN1 levels across multiple CRC models. Inhibition of MEK1/2, but not GSK3B, causes a reduction of AXIN1 transcript levels. While GSK3B inhibition results in rapid protein degradation of AXIN1, targeting of MEK1/2 alters neither protein stability nor post-translational modifications of AXIN1. Instead, MEK1/2 inhibition represses global translation via an mTOR dependent mechanism, which is sufficient to cause AXIN1 loss. Concordantly, mTOR inhibitors phenocopy the effect of MEK1/2 inhibitors on AXIN1 levels. Our study demonstrates that AXIN1 protein homeostasis is critically controlled by Ras-MAPK signaling at the level of protein synthesis, and that its perturbation by MEK1/2 inhibitors result in AXIN1 loss.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Colon Cancer

SUBMITTER: Robert Ihnatko

LAB HEAD: Dr. Jeroen Krijgsveld

PROVIDER: PXD067308 | Pride | 2026-06-03

REPOSITORIES: Pride

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			Action	DRS
	GSKi_AXIN1Ab_PG_Quant.tsv	Tabular
	GSKi_AXIN1Ab_PTM.tsv	Tabular
	GSKi_Chir_30m_AXIN1Ab_R1.raw	Raw
	GSKi_Chir_30m_AXIN1Ab_R2.raw	Raw
	GSKi_Chir_30m_AXIN1Ab_R3.raw	Raw

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MEK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis [RNASeq_SW480]

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