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Differential PKA activation and AKAP association determines cell fate in cancer cells

Erik D Hedrick1, Ekta Agarwal, Premila D Leiphrakpam

  • 1Eppley Cancer Center, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE 68198-5950, USA. mbrattain@unmc.edu.

Journal of Molecular Signaling
|October 3, 2013
PubMed
Abstract

Insights

Inhibition of Insulin-like Growth Factor 1 Receptor (IGF1R) in colorectal cancer (CRC) triggers cell death via a novel pathway involving cAMP-independent Protein Kinase A (PKA) activation. Conversely, IGF1R activation promotes cell survival through a cAMP-dependent PKA pathway.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Signaling

Background:

  • Colorectal cancer (CRC) malignancy is linked to Insulin-like Growth Factor 1 Receptor (IGF1R) signaling.
  • IGF1R antagonists are in clinical trials for cancer treatment.
  • A novel pathway involving cAMP-independent Protein Kinase A (PKA) activation by TGFβ signaling destabilizes the survivin/XIAP complex, increasing cell death.

Purpose of the Study:

  • To investigate the impact of IGF1R inhibition and activation on PKA activation.
  • To elucidate downstream cell survival signaling mechanisms regulated by IGF1R and PKA.

Main Methods:

  • Utilized the IGF1R kinase inhibitor OSI-906 to assess IGF1R inhibition effects on PKA activation and AKAP association.
  • Employed ligand-mediated IGF1R activation to analyze AKAP/PKA signaling and downstream survival effects.

Main Results:

  • IGF1R inhibition in CRC cells induces cell death via TGFβ-stimulated, cAMP-independent PKA activity, disrupting survivin/XIAP-mediated caspase inhibition.
  • Ligand-mediated IGF1R activation in CRC cells generates cAMP-dependent PKA activity, promoting cell survival by inhibiting caspases.
  • Two opposing cytoplasmic pathways utilizing PKA were identified, organized by different AKAP proteins (AKAP149 for apoptosis, Praja2 for survival), with opposing effects on cell fate.

Conclusions:

  • Identified two distinct cytoplasmic pathways mediated by PKA with opposing effects on cell survival and death in colorectal cancer.
  • Understanding IGF1R's role in PKA-mediated survival signaling offers potential for novel therapeutic strategies in cancer treatment.

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