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Carbon monoxide releasing molecule-2 CORM-2 represses global protein synthesis by inhibition of eukaryotic elongation

Christian Ingo Schwer1, Patrick Stoll, Sabine Rospert

  • 1Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetterstrasse 55, D-79106 Freiburg, Germany. christian.schwer@uniklinik-freiburg.de

The International Journal of Biochemistry & Cell Biology
|October 9, 2012
PubMed

Insights

Carbon monoxide (CO) releasing molecule-2 (CORM-2) inhibits global protein synthesis in pancreatic stellate cells by affecting key translational factors. This suggests therapeutic potential for CO-based therapies in fibrotic and hyperproliferative diseases.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Pharmacology

Background:

  • Carbon monoxide (CO) is an endogenous gaseous transmitter with known antiproliferative effects.
  • The impact of CO on cellular translational machinery, particularly in pancreatic stellate cells (PSCs), remains largely undescribed.
  • PSCs are key collagen-producing cells implicated in pancreatic fibrosis.

Purpose of the Study:

  • To investigate the effects of the CO-releasing molecule-2 (CORM-2) on translational signaling and protein synthesis in PSCs.
  • To elucidate the molecular mechanisms underlying CORM-2's impact on PSCs.
  • To explore the therapeutic potential of CORM-2 in conditions involving excessive protein synthesis or hyperproliferation.

Main Methods:

  • Isolation and incubation of rat PSCs with CORM-2.
  • Assessment of phosphorylation status of key translational factors including eukaryotic elongation factor 2 (eEF2), 4E-binding protein 1 (4E-BP1), eukaryotic initiation factor 2α (eIF2α), and eukaryotic initiation factor 4E (eIF4E).
  • Analysis of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway, intracellular calcium and cAMP levels, cell cycle regulatory proteins (cyclin D1, cyclin E, retinoblastoma protein Rb), and global protein synthesis.

Main Results:

  • CORM-2 prevented serum-induced decrease in eEF2 phosphorylation but inhibited 4E-BP1 phosphorylation.
  • CORM-2 treatment suppressed global protein synthesis in PSCs.
  • These effects were linked to inhibition of PI3K-Akt-mTOR signaling, increased intracellular calcium and cAMP, downregulation of cyclins D1 and E, and cell cycle arrest at G(0)/G(1) phase.

Conclusions:

  • CORM-2 modulates critical steps in translational signaling, leading to suppressed protein synthesis and cell growth arrest in PSCs.
  • CO releasing molecules like CORM-2 show promise for treating fibrosis, inflammation, cancer, and other pathologies characterized by excessive protein synthesis or hyperproliferation.
  • Prolonged exogenous CO application may pose risks to cellular protein homeostasis.

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