Human caspase 7 is positively controlled by SREBP-1 and SREBP-2.
Statins are lipid-lowering drugs that may help limit cancer occurrence in humans. They drive blockage of the mevalonate pathway, trigger cancer cell apoptosis in vitro and reduce tumour incidence in animals. We have shown in the present study that statins induced apoptosis in HGT-1 human gastric cancer cells, and this was prevented by intermediates of the cholesterol synthetic pathway. In addition, similarly to what we have reported previously for caspase 2 [Logette, Le Jossic-Corcos, Masson, Solier, Sequeira-Legrand, Dugail, Lemaire-Ewing, Desoche, Solary and Corcos (2005) Mol. Cell. Biol. 25, 9621-9631], caspase 7 may also be induced by statins and is under the positive control of SREBP (sterol-regulatory-element-binding protein)-1 and -2, major activators of cholesterol and fatty acid synthesis genes, in HGT-1 cells. Knocking down these proteins strongly reduced caspase 7 mRNA and protein expression, and chromatin immunoprecipitation analyses showed that the proximal promoter region of the CASP7 gene could bind either SREBP-1 or -2. Strikingly, cells selected to grow in the continuous presence of statins showed increased expression of caspase 7 mRNA and protein, which was maintained in the absence of statins for several weeks, suggesting that high expression of this caspase might participate in adaptation to blunting of the mevalonate pathway in this model. Taken together, our results show that caspase 7, as an SREBP-1/2 target, can be induced under mevalonate-restricting conditions, which might help overcome its shortage.
Gibot
Laure
L
INSERM, UMR 613, Université de Brest, 22 Avenue Camille Desmoulins, Brest Cedex 3, France.
Follet
Julie
J
Metges
Jean-Philippe
JP
Auvray
Pierrick
P
Simon
Brigitte
B
Corcos
Laurent
L
Le Jossic-Corcos
Catherine
C