Systemic targeting inhibitor of kappaB kinase inhibits melanoma tumor growth.
Constitutive activation of nuclear factor-kappaB (NF-kappaB) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of kappaB kinase (IKK) functions as a major mediator of NF-kappaB activation. Thus, development of an IKK-specific inhibitor has been a high priority, although it remains unclear whether systemic inhibition of IKK will provide therapeutic benefit. In this study, we show that inhibition of NF-kappaB activity in melanocytes that are persistently expressing an active H-Ras(V12) gene and are deficient in the tumor suppressors inhibitor A of cyclin-dependent kinase 4/alternative reading frame results in reduction of melanoma tumor growth in vivo. This effect is, at least in part, via regulation of NF-kappaB nuclear activation and RelA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKKalpha or IKKbeta. The ribozymes were placed in an EBV construct and delivered i.v. to nude mice bearing melanoma lesions, which developed after i.v. injection of H-Ras-transformed melanoma cells. Our in vivo data show that knockdown of endogenous IKKbeta significantly reduces the growth of the melanoma lesions and knockdown of either IKKalpha or IKKbeta prolongs the life span of immunocompetent mice.
Yang
Jinming
J
Department of Cancer Biology, Vanderbilt University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee, USA.
Pan
Wei-Hua
WH
Clawson
Gary A
GA
Richmond
Ann
A
D000818:Animals; D001483:Base Sequence; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D011905:Genes, ras; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D016337:RNA, Catalytic; C427204:hammerhead ribozyme; D051550:I-kappa B Kinase