There is increasing evidence that
statin treatment can be beneficial in certain
cancer patients. To determine if these benefits are a direct result of the
cholesterol-lowering effects of
statins or a result of secondary,
protein transcription effects, the impacts of
pravastatin and a
cholesterol sequestrating agent
methyl-beta-cyclodextrin (MbetaCD) on
mRNA expression in the
breast cancer cell MDA-MB-231 and the lung
carcinoma cell Calu-1 have been compared by microarray techniques. The effects of these agents on
cholesterol-rich rafts and caveolae, which have significance in
cancer signaling, have also been examined. Both treatments caused a general downregulation of not only signal transduction including
cancer pathway
proteins, but also apoptosis and
chemokine pathways, with
statins impacting 35 genes by twofold or greater in MDA-MB-231 and > 300 genes in Calu-1. These manifold dysregulations could also explain the various side effects reportedly caused by
statins. MbetaCD produced far fewer statistical events than
pravastatin in the
breast cancer line but many more in the lung cell line.
Pravastatin increased expression of CAV1 but caveolae density decreased and overall raft density was unaffected. MbetaCD also caused an increase in CAV1 expression and reduced the prevalence of both rafts and caveolae. It is proposed that sequestration of
cholesterol from the membrane by MbetaCD is not equivalent to blockade of the
cholesterol pathway and causes different effects on microdomain-mediated signal transduction dependant on the cell line. The profound effects of
statins on
mRNA expression can be explained by the failure of
caveolin-1 to properly complex with
cholesterol in an altered
sterol environment, with caveolae acting as the main loci for signaling directed towards those transcription processes unaffected by MbetaCD. Targeted inhibition of the postmevalonate pathway could offer an opportunity to specifically reduce caveolae-based signaling in
cancer cells. The observed impact of
pravastatin on gene expression may explain the pleiotropic effects of
statins when they are used as adjuvants in
chemotherapy and suggests impact on gene expression as a possible cause of side effects from
statin use.