Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-kappaB activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-kappaB-regulated gene expression and up-regulation of apoptosis.
Ras farnesyltransferase inhibitor (FTI) exhibit antiproliferative and antiangiogenic effects through a mechanism that is poorly understood. Because of the known role of Ras in the activation of transcription factor NF-kappaB and because NF-kappaB-regulated genes can control cell survival and angiogenesis, we postulated that FTI mediates its effects in part by modulating NF-kappaB activation. Therefore, in the present study we investigated the effect of FTI, SCH 66336, on NF-kappaB and NF-kappaB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. We demonstrate by DNA-binding assay that NF-kappaB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, cigarette smoke, okadaic acid, and H(2)O(2) was completely suppressed by SCH 66336; the suppression was not cell type-specific. This FTI suppressed the activation of IkappaBalpha kinase (IKK), thus abrogating the phosphorylation and degradation of IkappaBalpha. Additionally, TNF-activated Ras and SCH 66336 inhibited the activation. Also, overexpression of Ras (V12) enhanced TNF-induced NF-kappaB activation, and adenoviral dominant-negative Ras (N17) suppressed the activation, thus suggesting the critical role of Ras in TNF signaling. SCH 66336 also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-kappaB. The TNF-induced NF-kappaB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP1, IAP2, XIAP, Bcl-2, Bfl-1/A1, TRAF1, and FLIP were all down-regulated by SCH 66336, which potentiated apoptosis induced by TNF and doxorubicin. Overall, our results indicate that SCH 66336 inhibited activation of NF-kappaB and NF-kappaB-regulated gene expressions induced by carcinogens and inflammatory stimuli, which may provide a molecular basis for the ability of SCH 66336 to suppress proliferation and angiogenesis.
Takada
Yasunari
Y
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Khuri
Fadlo R
FR
Aggarwal
Bharat B
BB
D021581:Active Transport, Cell Nucleus; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D019169:Jurkat Cells; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D019319:Okadaic Acid / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012907:Smoking; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D002273:Carcinogens; D004247:DNA; D004791:Enzyme Inhibitors; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase; D016328:NF-kappa B; D019319:Okadaic Acid; D010880:Piperidines; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D018631:ras Proteins; C064911:p21(ras) farnesyl-protein transferase; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes