Abstract
The lipophilic statin lovastatin decreases cholesterol synthesis and is a safe and effective treatment for the prevention of cardiovascular diseases. Growing evidence points at antitumor potential of lovastatin. Therefore, understanding the molecular mechanism of lovastatin function in different cell types is critical to effective therapy design. In this study, we investigated the effects of lovastatin on the differentiation potential of human embryonic stem (hES) cells (H9 cell line). Multiparameter flow cytometric assay was used to detect changes in the expression of transcription factors characteristic of hES cells. We found that lovastatin treatment delayed NANOG downregulation during ectodermal and endodermal differentiation. Likewise, expression of ectodermal (SOX1 and OTX2) and endodermal (GATA4 and FOXA2) markers was higher in treated cells. Exposure of hES cells to lovastatin led to a minor decrease in the expression of SSEA-3 and a significant reduction in CD133 expression. Treated cells also formed fewer embryoid bodies than control cells. By analyzing hES with and without CD133, we discovered that CD133 expression is required for proper formation of embryoid bodies. In conclusion, lovastatin reduced the heterogeneity of hES cells and impaired their differentiation potential.
Highlights
Statins have been safely used for lowering cholesterol synthesis thereby preventing atherosclerotic cardiovascular diseases
Understanding the molecular mechanism of lovastatin function in different cell types is critical to effective therapy design
Prolonged exposure (24 to 48 hours) to lovastatin resulted in less compact colony structures, and the total number of cells was significantly lower compared to untreated human embryonic stem (hES) cells (Figures 1(b) and 1(d))
Summary
Statins have been safely used for lowering cholesterol synthesis thereby preventing atherosclerotic cardiovascular diseases. A growing body of evidence points to the potential effectiveness of statins in ameliorating other medical conditions such as cancer. Statin treatment of cancer patients has been linked to low death rate, longer survival, and lower risk of venous thromboembolism [1, 2]. Several in vitro studies exploring the mechanism of statins’ function have revealed that in addition to inhibiting the mevalonate pathway, statins affect signalling pathways regulating cell proliferation and apoptosis. It has been shown that mevalonate pathway inhibition influences epigenetic mechanisms behind oncogenesis [3]. Epigenetic mechanisms have been shown to regulate either directly or indirectly an intense cross-talk between signalling pathways that affect growth, differentiation, and apoptosis. The effects of statins could be very wide-ranging, and their impact on various cell types needs thorough investigation
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