Inhibitors of both nuclear factor-κB and activator protein-1 activation block the neoplastic transformation response

Jian-Jian Li, Chandra Westergaard, Paritosh Ghosh, Nancy H. Colburn

Research output: Contribution to journalArticle

205 Scopus citations

Abstract

Cross-coupling of active protein-1 tAP-1) and nuclear factor (NF)-κB has been reported. In the present study, we investigated the possibility that both of these two transcription factors might contribute to the process of tumor promoter-induced transformation. To establish a stable reporter cell system, two reporter genes were stably transfected into a JB6 mouse tumor promotion-sensitive (P+) cell line: a luciferase reporter controlled by a collagenase AP-1 sequence and a chloramphenicol acetyltransferase reporter controlled by an interleukin 6 NF-κB sequence. This double-reporter cell line maintained the phenotype of tumor promotion sensitivity and was able to report basal or induced AP-1 and NF-κB transactivation. The cytokine tumor promoter tumor necrosis factor (TNF)-α transactivated NF-κB and AP-1 for both DNA binding and transcriptional activity, Pyrrolidine dithiocarbamate, an antioxidant that acts as an NF-κB inhibitor, efficiently inhibited 12-O- tetradecanoylphorbol-13-acetate (TPA) or TNF-α induced NF-κB as well as AP- 1 transactivation and cell transformation, suggesting dependency of transformation on both transcription factors. The AP-1 transrepressing- retinoid SR11302 transrepressed AP-1 and cell transformation when these were TPA induced but not when TNF-α induced, indicating different signaling pathways for TNF-α and TPA. Supershift electrophoresis mobility shift assay revealed that Jun B and c-Jun were absent from the AP-1/DNA complex following TNF-α but present following TPA treatment. Together, these results suggest that both AP-1 and NF-κB activation may be required for transformation whether induced by TPA or by TNF, and the differential sensitivity of TPA and TNF-α-induced transformation to inhibition by a retinoid might be explained by differences in the composition of the DNA-bound AP-1 complexes.

Original languageEnglish (US)
Pages (from-to)3569-3576
Number of pages8
JournalCancer Research
Volume57
Issue number16
StatePublished - Aug 15 1997
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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