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PI3Kα Translocation Mediates Nuclear PtdIns(3,4,5)P3 Effector Signaling in Colorectal Cancer

Michelle Palmieri1, Bruno Catimel1, Dmitri Mouradov1

  • 1Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Molecular & Cellular Proteomics : MCP
|March 17, 2023
PubMed

Insights

This study reveals that PI3Kα translocates to the nucleus in colorectal cancer (CRC) cells, generating nuclear phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to influence RNA metabolism and pre-mRNA splicing.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Signaling

Background:

  • The canonical PI3Kα signaling pathway primarily involves phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) generation at the plasma membrane or endosomes.
  • Colorectal cancer (CRC) progression is linked to dysregulated signaling pathways, but the precise localization and function of PI3Kα within cancer cells remain incompletely understood.

Purpose of the Study:

  • To investigate the subcellular localization of PI3Kα in CRC cells and identify its nuclear targets.
  • To elucidate the functional role of nuclear PI3Kα signaling in CRC, particularly concerning RNA metabolism.
  • To correlate nuclear PI3Kα expression with clinical parameters in CRC patients.

Main Methods:

  • Analysis of PI3Kα distribution in CRC cell lines, revealing both plasma membrane and nuclear localization.
  • Utilizing importin β-dependent pathway for nuclear translocation.
  • Employing PtdIns(3,4,5)P3 affinity capture mass spectrometry to identify nuclear PtdIns(3,4,5)P3-binding proteins (interactome).
  • Performing splicing reporter assays and SC-35 foci staining to assess pre-mRNA splicing modulation.
  • Examining nuclear p110α staining in patient tumor samples.

Main Results:

  • CRC cell lines display diverse PI3Kα localization, including significant nuclear presence.
  • Identified 867 potential nuclear PtdIns(3,4,5)P3 effector proteins, many with noncanonical PtdIns(3,4,5)P3-binding domains.
  • The nuclear PtdIns(3,4,5)P3 interactome is enriched in proteins involved in RNA metabolism.
  • Nuclear PI3Kα signaling, stimulated by epidermal growth factor, modulates pre-mRNA splicing.
  • Nuclear p110α expression in tumors correlates with lower T stage and mucinous histology.

Conclusions:

  • PI3Kα nuclear translocation is a key mechanism in CRC, establishing nuclear PtdIns(3,4,5)P3 effector signaling.
  • Nuclear PI3Kα signaling plays a significant role in regulating RNA metabolism and pre-mRNA splicing in CRC.
  • Nuclear PI3Kα localization serves as a potential prognostic biomarker in colorectal cancer.
Keywords:
PI3KαPtdIns(3,4,5)P(3) interactomecolorectal cancernuclear import pathwaypre-mRNA splicing

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