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.

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.

• Authors: Laura Cesaratto, Erika Codarin, Carlo Vascotto, Antonio Leonardi, Mark R Kelley, Claudio Tiribelli, Gianluca Tell
• Journal: PloS one (PLoS One) Vol. 8 Issue 8 Pg. e70909 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23967134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoquinones
• Fatty Acids
• Interleukin-8
• NF-kappa B
• Propionates
• Tumor Necrosis Factor-alpha
• E 3330
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• Benzoquinones (pharmacology)
• Carcinoma, Hepatocellular (genetics, metabolism)
• Cell Line, Tumor
• DNA-(Apurinic or Apyrimidinic Site) Lyase (genetics, metabolism)
• Fatty Acids (metabolism)
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Humans
• Interleukin-8 (biosynthesis, genetics)
• Liver Neoplasms (genetics, metabolism)
• NF-kappa B (metabolism)
• Oxidation-Reduction (drug effects)
• Promoter Regions, Genetic
• Propionates (pharmacology)
• Transcriptional Activation (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)