en
Scientific article
Open access
English

Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth

Published inNature communications, vol. 13, no. 1, 674
Publication date2022-02-03
First online date2022-02-03
Abstract

Conductin/axin2 is a scaffold protein negatively regulating the pro-proliferative Wnt/β-catenin signaling pathway. Accumulation of scaffold proteins in condensates frequently increases their activity, but whether condensation contributes to Wnt pathway inhibition by conductin remains unclear. Here, we show that the Gαi2 subunit of trimeric G-proteins induces conductin condensation by targeting a polymerization-inhibiting aggregon in its RGS domain, thereby promoting conductin-mediated β-catenin degradation. Consistently, transient Gαi2 expression inhibited, whereas knockdown activated Wnt signaling via conductin. Colorectal cancers appear to evade Gαi2-induced Wnt pathway suppression by decreased Gαi2 expression and inactivating mutations, associated with shorter patient survival. Notably, the Gαi2-activating drug guanabenz inhibited Wnt signaling via conductin, consequently reducing colorectal cancer growth in vitro and in mouse models. In summary, we demonstrate Wnt pathway inhibition via Gαi2-triggered conductin condensation, suggesting a tumor suppressor function for Gαi2 in colorectal cancer, and pointing to the FDA-approved drug guanabenz for targeted cancer therapy.

eng
Keywords
  • Animals
  • Axin Protein / genetics
  • Axin Protein / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Female
  • GTP-Binding Protein alpha Subunit, Gi2 / genetics
  • Gene Expression Regulation, Neoplastic
  • Guanabenz / pharmacology
  • HEK293 Cells
  • Humans
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mutation
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / genetics
  • Xenograft Model Antitumor Assays / methods
  • Beta Catenin / genetics
  • Beta Catenin / metabolism
  • GTP-Binding Protein alpha Subunit,Gi2/metabolism
  • Adrenergic alpha-2 Receptor Agonists/pharmacology
Citation (ISO format)
MIETE, Cezanne et al. Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth. In: Nature communications, 2022, vol. 13, n° 1, p. 674. doi: 10.1038/s41467-022-28286-9
Main files (1)
Article (Published version)
Secondary files (14)
Identifiers
ISSN of the journal2041-1723
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151downloads

Technical informations

Creation2022/04/04 12:28:00
First validation2022/04/04 12:28:00
Update time2023/03/16 06:21:44
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