Abstract
Recent studies have demonstrated that statins reduce cell viability and induce apoptosis in various types of cancer cells. The molecular mechanisms underlying these effects are poorly understood. The JAK/STAT pathway plays an important role in the regulation of proliferation and apoptosis in many tissues, and its deregulation is believed to be involved in tumorigenesis and cancer. The physiological activation of STAT proteins by GH is rapid but transient in nature and its inactivation is regulated mainly by the expression of SOCS proteins. UMR-106 osteosarcoma cells express a GH-responsive JAK2/STAT5 signaling pathway, providing an experimental model to study the influence of statins on this system. In this study we investigated the actions of simvastatin on cell proliferation, migration, and invasion on UMR-106 cells and examined whether alterations in GH-stimulated JAK/STAT/SOCS signaling may be observed. Results showed that treatment of osteosarcoma cells with simvastatin at 3 to 10 µM doses decreases cell proliferation, migration, and invasion in a time- and dose-dependent manner. At the molecular level, although the mechanisms used by simvastatin are not entirely clear, the effect of the statin on the reduction of JAK2 and STAT5 phosphorylation levels may partially explain the decrease in the GH-stimulated STAT5 transcriptional activity. This effect correlated with a time- and dose-dependent increase of SOCS-3 expression levels in cells treated with simvastatin, a regulatory role that has not been previously described. Furthermore, the finding that simvastatin is capable of inducing SOCS-3 and CIS genes expression shows the potential of the JAK/STAT pathway as a therapeutic target, reinforcing the efficacy of simvastatin as chemotherapeutic drug for the treatment of osteosarcoma.
Highlights
Statins inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate biosynthetic pathway, and source of intermediates involved in protein farnesylation and geranylation [1]
We studied the effects of simvastatin on proliferation of osteosarcoma cells, by measuring the amount of BrdU incorporated into DNA (Fig. 1)
We found a significant reduction in cell proliferation after 24 h treatment with 10 mM simvastatin (p,0.01)
Summary
Statins inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate biosynthetic pathway, and source of intermediates involved in protein farnesylation and geranylation [1] These posttranslational modifications are vital for proper functioning of proteins Ras, Rho, Rac, and other small GTPases, which are involved in the regulation of several biological processes including cell proliferation, migration, viability, cell cycle, and invasiveness [2], making them important targets for understanding statin effects. RhoA and Ras family proteins have been the most investigated targets in statin research, several studies have linked statins to the Janus Kinases/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway This signaling pathway is an important regulator of cell proliferation, differentiation, survival, motility, and apoptosis [9]. Statins, including simvastatin, inhibited the JAK/STAT signaling pathway in cardiomyocytes [15] and vascular endothelial cells [16] besides upregulating mRNA and protein expression of SOCS-3 and SOCS-7 in the macrophage cell line RAW264.7 [17,18]
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