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Regulation of anoikis by Cdc42 and Rac1

Tzu-Ling Cheng1, Marc Symons, Tzuu-Shuh Jou

  • 1Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.

Experimental Cell Research
|April 20, 2004
PubMed

Insights

Constitutive activation of Cdc42 inhibits anoikis, a form of cell death, in epithelial cells. This survival is mediated by Rac1 and the PI3K pathway, highlighting Cdc42

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Ras family small GTPases are critical in malignant transformation.
  • Rho subfamily members, including Cdc42, significantly contribute to cancer progression.
  • Anchorage-independent growth and anoikis resistance are hallmarks of transformed epithelial cells.

Purpose of the Study:

  • To investigate the role of constitutively activated Cdc42 in anoikis inhibition in Madin-Darby canine kidney (MDCK) epithelial cells.
  • To elucidate the signaling pathways involved in Cdc42-mediated anoikis resistance.
  • To explore the interplay between Cdc42, Rac1, and the PI3K pathway in epithelial cell survival.

Main Methods:

  • Utilized a double regulatory expression system for activated Cdc42 and Rac1.
  • Employed Madin-Darby canine kidney (MDCK) epithelial cells.
  • Assessed cell survival under suspension conditions and anoikis inhibition.
  • Investigated the involvement of MAPK pathways (ERK, JNK, p38) and phosphatidylinositol 3-kinase (PI3K).
  • Examined the effect of Latrunculin B on cell survival.

Main Results:

  • Constitutively active Cdc42 inhibits anoikis in MDCK cells.
  • Activated Cdc42 stimulates ERK, JNK, and p38 MAPK pathways, but their inhibition does not affect Cdc42-stimulated cell survival.
  • Inhibition of the PI3K pathway abolishes the protective effect of Cdc42 on anoikis.
  • Cdc42-stimulated cell survival is partly mediated by Rac1, involving a positive feedback loop with PI3K.
  • The survival functions of Cdc42 and Rac1 are abrogated by Latrunculin B, indicating a role for the actin cytoskeleton.

Conclusions:

  • Cdc42 plays a significant role in anchorage-independent survival of epithelial cells.
  • Cdc42-mediated anoikis resistance involves Rac1 and the PI3K pathway.
  • A positive feedback loop between Rac1 and PI3K contributes to epithelial cell survival.
  • The actin cytoskeleton is crucial for mediating survival signaling activated by Cdc42 and Rac1.

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