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A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways

V Mamidipudi1, C A Cartwright

  • 1Department of Medicine, Stanford University, Stanford, CA 94305-5187, USA.

Oncogene
|September 22, 2009
PubMed

Insights

Receptor for activated C kinase 1 (RACK1) inhibits human colon cell growth and triggers apoptosis by suppressing Src activity and blocking the Akt survival pathway. These findings suggest RACK1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • RACK1 previously shown to regulate human colon cell growth by suppressing Src activity at G(1) and mitotic checkpoints.
  • RACK1's role in apoptosis and its precise molecular mechanisms in colon cells require further elucidation.

Purpose of the Study:

  • To investigate the role of RACK1 in inducing apoptosis in human colon cells.
  • To elucidate the molecular pathways, including Src and Akt signaling, involved in RACK1-mediated apoptosis.
  • To explore the potential of RACK1 as a therapeutic target in colon cancer.

Main Methods:

  • Analysis of RACK1's effects on apoptosis-related gene expression (Bcl-2, Bcl-X(L), Bim).
  • Mitochondrial pathway analysis: Bax and Bim targeting, Bax oligomerization, mitochondrial membrane depolarization, and cytochrome c release.
  • Assessment of caspase activation (caspase-9, caspase-3).
  • Investigation of RACK1's impact on the Akt cell survival pathway and FOXO3 activation.

Main Results:

  • RACK1 induces apoptosis in colon cells, partly by inhibiting Src.
  • RACK1 downregulates anti-apoptotic proteins (Bcl-2, Bcl-X(L)) and upregulates pro-apoptotic protein Bim.
  • RACK1 promotes mitochondrial cell death by targeting Bax and Bim to mitochondria, inducing Bax oligomerization, and releasing cytochrome c, leading to caspase activation.
  • RACK1 inhibits the Akt survival pathway, activating FOXO3, which contributes to apoptosis and G(1) arrest.
  • Bax and Bim are essential for RACK1-mediated mitochondrial cell death.

Conclusions:

  • RACK1 plays a dual role in colon cells: inhibiting growth and inducing apoptosis.
  • RACK1-mediated apoptosis occurs through intrinsic mitochondrial and extrinsic Akt/FOXO3 pathways, with Src inhibition being a common mechanism.
  • RACK1's ability to inhibit growth and induce death presents a promising strategy for developing novel colon cancer therapies.

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