Systemic targeting inhibitor of κB kinase inhibits melanoma tumor growth

Jinming Yang, Wei Hua Pan, Gary A. Clawson, Ann Richmond

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Constitutive activation of nuclear factor-κB (NF-κB) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of κB kinase (IKK) functions as a major mediator of NF-κB 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-κB activity in melanocytes that are persistently expressing an active H-RasV12 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-κB nuclear activation and RelA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKKα or IKKβ. 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 IKKβ significantly reduces the growth of the melanoma lesions and knockdown of either IKKα or IKKβ prolongs the life span of immunocompetent mice.

Original languageEnglish (US)
Pages (from-to)3127-3134
Number of pages8
JournalCancer Research
Volume67
Issue number7
DOIs
StatePublished - Apr 1 2007

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Melanoma
Phosphotransferases
Growth
Neoplasms
Cyclin-Dependent Kinase 4
Reading Frames
Catalytic RNA
Melanocytes
Human Herpesvirus 4
Nude Mice
Carcinogenesis
Phosphorylation
Injections
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yang, Jinming ; Pan, Wei Hua ; Clawson, Gary A. ; Richmond, Ann. / Systemic targeting inhibitor of κB kinase inhibits melanoma tumor growth. In: Cancer Research. 2007 ; Vol. 67, No. 7. pp. 3127-3134.
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Systemic targeting inhibitor of κB kinase inhibits melanoma tumor growth. / Yang, Jinming; Pan, Wei Hua; Clawson, Gary A.; Richmond, Ann.

In: Cancer Research, Vol. 67, No. 7, 01.04.2007, p. 3127-3134.

Research output: Contribution to journalArticle

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