Specific Inhibition of the Redox Activity of Ape1/Ref-1 by E3330 Blocks Tnf-Α-Induced Activation of Il-8 Production in Liver Cancer Cell Lines

Laura Cesaratto, Erika Codarin, Carlo Vascotto, Antonio Leonardi, Mark Kelley, Claudio Tiribelli, Gianluca Tell

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

APE1/Ref-1 is a main regulator of cellular response to oxidative stress via DNA-repair function and co-activating activity on the NF-κB transcription factor. APE1 is central in controlling the oxidative stress-based inflammatory processes through modulation of cytokines expression and its overexpression is responsible for the onset of chemoresistance in different tumors including hepatic cancer. We examined the functional role of APE1 overexpression during hepatic cell damage related to fatty acid accumulation and the role of the redox function of APE1 in the inflammatory process. HepG2 cells were stably transfected with functional and non-functional APE1 encoding plasmids and the protective effect of APE1 overexpression toward genotoxic compounds or FAs accumulation, was tested. JHH6 cells were stimulated with TNF-α in the presence or absence of E3330, an APE1 redox inhibitor. IL-8 promoter activity was assessed by a luciferase reporter assay, gene expression by Real-Time PCR and cytokines (IL-6, IL-8, IL-12) levels measured by ELISA. APE1 over-expression did not prevent cytotoxicity induced by lipid accumulation. E3330 treatment prevented the functional activation of NF-κB via the alteration of APE1 subcellular trafficking and reduced IL-6 and IL-8 expression induced by TNF-α and FAs accumulation through blockage of the redox-mediated activation of NF-κB. APE1 overexpression observed in hepatic cancer cells may reflect an adaptive response to cell damage and may be responsible for further cell resistance to chemotherapy and for the onset of inflammatory response. The efficacy of the inhibition of APE1 redox activity in blocking TNF-α and FAs induced inflammatory response opens new perspectives for treatment of inflammatory-based liver diseases.

Original languageEnglish
Article numbere70909
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 15 2013

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liver neoplasms
Liver Neoplasms
Liver
hepatocytes
Oxidation-Reduction
interleukin-8
Chemical activation
Interleukin-8
Cells
cell lines
Cell Line
Oxidative stress
interleukin-6
Hepatocytes
Interleukin-6
Oxidative Stress
cytokines
oxidative stress
inflammation
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Specific Inhibition of the Redox Activity of Ape1/Ref-1 by E3330 Blocks Tnf-Α-Induced Activation of Il-8 Production in Liver Cancer Cell Lines. / Cesaratto, Laura; Codarin, Erika; Vascotto, Carlo; Leonardi, Antonio; Kelley, Mark; Tiribelli, Claudio; Tell, Gianluca.

In: PLoS One, Vol. 8, No. 8, e70909, 15.08.2013.

Research output: Contribution to journalArticle

Cesaratto, Laura ; Codarin, Erika ; Vascotto, Carlo ; Leonardi, Antonio ; Kelley, Mark ; Tiribelli, Claudio ; Tell, Gianluca. / Specific Inhibition of the Redox Activity of Ape1/Ref-1 by E3330 Blocks Tnf-Α-Induced Activation of Il-8 Production in Liver Cancer Cell Lines. In: PLoS One. 2013 ; Vol. 8, No. 8.
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