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Suppression of polyamine catabolism by activated Ki-ras in human colon cancer cells

Natalia A Ignatenko1, Naveen Babbar, Dipti Mehta

  • 1Department of Cell Biology, Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.

Molecular Carcinogenesis
|January 30, 2004
PubMed

Insights

Mutated Ki-ras oncogene suppresses spermidine/spermine N1-acetyltransferase (SSAT) expression in colon cancer cells. This occurs via the peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathway, impacting polyamine metabolism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Gastrointestinal tumorigenesis involves complex genetic and metabolic alterations.
  • The Ki-ras oncogene plays a critical role in cell proliferation and differentiation.
  • Polyamines are essential for cell growth, and their dysregulation is linked to cancer.

Purpose of the Study:

  • To investigate the impact of activated Ki-ras on polyamine metabolism in colon adenocarcinoma cells.
  • To elucidate the molecular mechanisms by which Ki-ras influences key enzymes in polyamine catabolism.
  • To explore the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in Ki-ras-mediated gene regulation.

Main Methods:

  • Expression of activated Ki-ras in Caco-2 colon cancer cells.
  • Analysis of spermidine/spermine N1-acetyltransferase (SSAT) gene transcription.
  • Gene expression profiling using cDNA microarrays.
  • Investigation of the peroxisome proliferator-activated receptor gamma (PPARgamma) response element (PPRE) in the SSAT gene promoter.
  • Pharmacological manipulation using a PPARgamma ligand and a MEK1/2 inhibitor.

Main Results:

  • Activated Ki-ras expression led to suppressed SSAT transcription in Caco-2 cells.
  • Ki-ras transfection decreased the expression of PPARgamma.
  • The SSAT promoter activity was restored by PPARgamma re-expression or ligand treatment.
  • MAPK pathway inhibition (PD98059) induced both PPARgamma and SSAT gene transcription.

Conclusions:

  • Mutated Ki-ras suppresses SSAT expression through a transcriptional mechanism.
  • The PPARgamma signaling pathway is a key mediator of Ki-ras effects on SSAT.
  • Mitogen-activated protein kinases (MAPKs) are involved in the regulation of SSAT by PPARgamma.

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