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Simvastatin Potentiates TNF--Induced Apoptosis through the Down-Regulation of NF-B-Dependent Antiapoptotic Gene Products: Role of IB Kinase and TGF--Activated Kinase-1¹

Cytokine Research Laboratory, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

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--induced cell signaling. We found that simvastatin potentiated the apoptosis induced by TNF- 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 (Bcl-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-B. We found that simvastatin inhibited TNF--induced NF-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-B activation. Simvastatin inhibited TNF--induced IB kinase activation, which led to inhibition of IB phosphorylation and degradation, suppression of p65 phosphorylation, and translocation to the nucleus. NF-B-dependent reporter gene expression induced by TNF-, TNFR1, TNFR-associated death domain protein, TNFR-associated factor 2, TGF--activated kinase 1, receptor-interacting protein, NF-B-inducing kinase, and IB kinase was abolished by simvastatin. Overall, our results provide novel insight into the role of simvastatin in potentially preventing and treating cancer through modulation of IB kinase and NF-B-regulated gene products.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by the Clayton Foundation for Research (to B.B.A.), a P01 Grant (CA91844) from the National Institutes of Health on Lung Chemoprevention (to B.B.A.), and a P50 Head and Neck Specialized Programs of Research Excellence grant from the National Institutes of Health (to B.B.A.).

² Address correspondence and reprint requests to Dr. Bharat B. Aggarwal, Department of Experimental Therapeutics, Unit 143, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail address: aggarwal{at}mdanderson.org

³ Abbreviations used in this paper: HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; cFLIP, cellular FLIP; COX-2, cyclooxygenase-2; IKK, IB kinase; MMP-9, matrix mellatoproteinase-9; NIK, NF-B-inducing kinase; PARP, poly(ADP-ribose) polymerase; PIS, preimmune sera; SEAP, secretory alkaline phosphatase; TAB, TAK1-binding protein; TRADD, TNFR-associated death domain; TRAF2, TNFR-associated factor; TAK, TGF--activated kinase; VEGF, vascular endothelial cell growth factor.

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