Simvastatin potentiates TNF-α-induced apoptosis through the down-regulation of NF-κB-dependent antiapoptotic gene products:: Role of IκBα kinase and TGF-β-activated kinase-1

Numerous recent reports suggest that statins (hydroxy-3-methylglutaryl-CoA reductase inhibitors) exhibit potential to suppress tumorigenesis through a mechanism that is not fully understood. Therefore, in this article, we investigated the effects of simvastatin on TNF-alpha-induced cell signaling. We found that simvastatin potentiated the apoptosis induced by TNF-alpha as indicated by intracellular esterase activity, caspase activation, TUNEL, and annexin V staining. This effect of simvastatin correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1 and cyclooxygenase-2), cell survival (Bel-2, Bcl-x(L,) cellular FLIP, inhibitor of apoptosis protein 1, inhibitor of apoptosis protein 2, and survivin), invasion (matrix mellatoproteinase-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor); all known to be regulated by the NF-kappa B. We found that simvastatin inhibited TNF-alpha-induced NF-kappa B activation, and L-mevalonate reversed the suppressive effect, indicating the role of hydroxy-3-methylglutaryl-CoA reductase. Simvastatin suppressed not only the inducible but also the constitutive NF-kappa B activation. Simvastatin inhibited TNF-alpha-induced l kappa B alpha kinase activation, which led to inhibition of I kappa B alpha phosphorylation and degradation, suppression of p65 phosphorylation, and translocation to the nucleus. NF-kappa B-dependent reporter gene expression induced by TNF-alpha, TNFR1, TNFR-associated death domain protein, TNFR-associated factor 2, TGF-beta-activated kinase 1, receptor-interacting protein, NF-kappa B-inducing kinase, and I kappa B kinase beta was abolished by simvastatin. Overall, our results provide novel insight into the role of simvastatin in potentially preventing and treating cancer through modulation of I kappa B kinase and NF-kappa B-regulated gene products.