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Effects of cyclopentenone prostaglandins and related compounds on insulin-like growth factor-I and Waf1 gene

T Bui1, D S Straus

  • 1Biology Department, University of California, Riverside 92521-0121, USA.

Biochimica Et Biophysica Acta
|April 18, 1998
PubMed

Insights

Cyclopentenone prostaglandins regulate gene expression, impacting cell growth and tumorigenicity. Glutathione conjugation influences these effects, with unsaturated carbonyl compounds being key regulators.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Prostaglandin Signaling

Background:

  • The precise molecular mechanisms by which cyclopentenone prostaglandins (PGA and PGJ series) inhibit cell growth and tumorigenicity remain largely unknown.
  • These prostaglandins may exert their effects through the specific regulation of genes involved in cell growth and stress responses.

Purpose of the Study:

  • To investigate the ability of various prostaglandins to modulate the expression of insulin-like growth factor-I (IGF-I) and Waf1 genes in C6 rat glioma cells.
  • To elucidate the role of glutathione in mediating the gene regulatory effects of prostaglandins, particularly PGA2.
  • To determine the structural requirements for prostaglandin-mediated gene regulation, focusing on the alpha, beta-unsaturated carbonyl moiety.

Main Methods:

  • Treatment of C6 rat glioma cells with a series of prostaglandins (PGJ2, PGA1, PGA2, PGD2, PGE2).
  • Quantification of IGF-I and Waf1 gene expression levels.
  • Manipulation of cellular glutathione levels using N-acetyl-L-cysteine (augmentation) and buthionine sulfoximine (depletion).
  • Testing of simpler cyclic and non-cyclic compounds containing alpha, beta-unsaturated carbonyls (2-cyclopenten-1-one, 4-cyclopentene-1,3-dione, diethyl maleate).

Main Results:

  • Prostaglandins PGJ2, PGA1, PGA2, and PGD2 significantly repressed IGF-I gene expression, with varying potencies.
  • Most tested prostaglandins, except PGE2, induced Waf1 gene expression, exhibiting a different potency order than for IGF-I repression.
  • Glutathione conjugation was found to attenuate the effects of PGA2 on IGF-I and Waf1 expression, while depletion potentiated these effects.
  • 2-Cyclopenten-1-one, 4-cyclopentene-1,3-dione, and diethyl maleate demonstrated the ability to repress IGF-I and induce Waf1 gene expression, highlighting the importance of the alpha, beta-unsaturated carbonyl group.

Conclusions:

  • Cyclopentenone prostaglandins differentially regulate IGF-I and Waf1 gene expression, suggesting distinct intracellular signaling pathways.
  • Glutathione conjugation plays a protective role against prostaglandin-mediated gene regulation.
  • The presence of an alpha, beta-unsaturated carbonyl group is essential for the observed effects on IGF-I and Waf1 gene expression, irrespective of a cyclic structure.

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