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Role of phosphoinositide 3OH-kinase in autocrine transformation by PDGF-BB

T Rosenmüller1, K Rydh, E Nånberg

  • 1Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Sweden.

Journal of Cellular Physiology
|July 27, 2001
PubMed

Insights

Phosphoinositide 3OH-kinases (PI3K) are crucial for cell transformation, driving altered morphology and migration. Inhibiting PI3K with LY294002 reversed these transformed characteristics in murine fibroblasts.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Phosphoinositide 3OH-kinases (PI3K) are lipid kinases regulating key cellular processes like migration, cytoskeletal rearrangements, and survival.
  • These processes are critical hallmarks of cellular transformation and cancer development.

Purpose of the Study:

  • To investigate the functional role of PI3K in the development of transformed morphology and migratory responses in murine fibroblasts.
  • To elucidate the downstream signaling pathways involved in PI3K-mediated transformation.

Main Methods:

  • Utilized specific PI3K inhibitor LY294002 on NIH/sis and COL1A1/NIH3T3 murine fibroblast cell lines.
  • Stimulated cells via autocrine expression of platelet-derived growth factor-BB (PDGF-BB).
  • Assessed morphological changes, density-independent growth, focus formation, and random cell migration.

Main Results:

  • Prolonged treatment with LY294002 reversed transformed morphology, inhibited density-independent growth, and prevented focus formation.
  • Functional PI3K activity was essential for the development of transformed morphology in both cell lines.
  • LY294002 treatment completely disrupted random cell migration.
  • Activation of the small GTPase Rac was identified as a prerequisite for the transformation signal downstream of PI3K.
  • Evidence of a suramin-insensitive PI3K activity was observed, potentially linked to intracellular PDGF receptor pools.

Conclusions:

  • Intact PI3K activity is indispensable for the morphological alterations characteristic of PDGF-induced autocrine transformation.
  • PI3K signaling is a critical regulator of cell migration and survival in the context of cellular transformation.
  • Targeting PI3K may represent a therapeutic strategy to revert or inhibit cancer cell phenotypes.

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