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Human caspase 7 is positively controlled by SREBP-1 and SREBP-2

Laure Gibot1, Julie Follet, Jean-Philippe Metges

  • 1INSERM, UMR 613, Université de Brest, 22 Avenue Camille Desmoulins, Brest Cedex 3, France.

The Biochemical Journal
|March 28, 2009
PubMed

Insights

Statins induce apoptosis in gastric cancer cells by blocking the mevalonate pathway. This process involves caspase 7, regulated by sterol-regulatory-element-binding protein (SREBP)-1 and -2, potentially aiding adaptation to mevalonate restriction.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Statins are lipid-lowering drugs with potential anticancer effects.
  • Statins inhibit the mevalonate pathway, inducing apoptosis in cancer cells.
  • Previous research indicated caspase 2 involvement in statin-induced apoptosis.

Purpose of the Study:

  • To investigate the role of caspase 7 in statin-induced apoptosis in HGT-1 human gastric cancer cells.
  • To determine the regulation of caspase 7 by sterol-regulatory-element-binding protein (SREBP)-1 and -2.
  • To explore the adaptive response of cancer cells to mevalonate pathway inhibition by statins.

Main Methods:

  • Induction of apoptosis in HGT-1 cells using statins.
  • Assessment of apoptosis prevention by cholesterol synthetic pathway intermediates.
  • Analysis of caspase 7 expression and its regulation by SREBP-1 and -2 via gene silencing and chromatin immunoprecipitation.
  • Selection of cells for growth in the presence of statins to study adaptation.

Main Results:

  • Statins induced apoptosis in HGT-1 cells, preventable by cholesterol pathway intermediates.
  • Caspase 7 expression was induced by statins and positively regulated by SREBP-1 and -2.
  • Knockdown of SREBP-1/-2 reduced caspase 7 mRNA and protein levels.
  • Chromatin immunoprecipitation confirmed SREBP-1/-2 binding to the CASP7 gene promoter.
  • Cells adapted to statins exhibited sustained high expression of caspase 7.

Conclusions:

  • Caspase 7 is a target of SREBP-1/-2 and is induced under mevalonate-restricting conditions.
  • Statin-induced caspase 7 expression may contribute to cancer cell adaptation to mevalonate pathway blunting.
  • These findings highlight a novel mechanism in statin's potential anticancer activity.

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