The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression

Nath, Somsubhra; Roychoudhury, Shrabasti; Kling, Matthew J.; Song, Heyu; Biswas, Pranjal; Shukla, Ashima; Band, Hamid; Joshi, Shantaram S.; Bhakat, Kishor K.

doi:10.1016/j.cellsig.2017.07.019

Cited by 32 publications

(44 citation statements)

References 65 publications

(116 reference statements)

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“…In order to evaluate a possible role for secreted APE1 in HCC, we tested whether exogenous addition of recombinant purified APE1 (rAPE1) may trigger a pro-inflammatory status in JHH-6 HCC cell line, as recently demonstrated in human monocytes cell lines [19]. In addition to the wild-type protein (rAPE1 WT ), we used an acetylated-mimicking mutant on residues 27, 31, 32, 35 (rAPE1 K4pleA ), in which Lys residues have been replaced by Ala, as described before [23, 24] and whose relevance in cancer have been recently demonstrated [22] (Supplementary Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…Other recent data demonstrated that the redox-function of APE1 may contribute to the control of the inflammatory response by inhibiting the TNF-α-induced endothelial inflammation via thiol-disulfide exchange in TNFR [18]. Moreover, very recently, a role for extracellular APE1 in the control of early stages of inflammation processes has been proposed [19]. Treatment of human THP-1 and RAW264.7 monocytes with rAPE1 increased the expression and secretion of the pro-inflammatory cytokine IL-6, through the involvement of NF-κB transcriptional activation, eliciting an autocrine/paracrine cellular response in a functional feedforward loop between APE1 and IL-6 regulation.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the chemotherapy-naïve serum APE1 level, which correlates with its tissue level, is inversely associated with progression-free survival of platinum-containing doublet chemotherapy; whereas post-treatment serum APE1 level is inversely associated with overall survival [16]. Interestingly, increasing evidences support the finding that extracellular APE1 secretion is a common feature of cancer cells, while the biological meaning remains to be elucidated but could be associated to triggering the inflammatory response of cancer microenvironment [17–19].…”

Section: Introductionmentioning

confidence: 99%

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Serum AP-endonuclease 1 (sAPE1) as novel biomarker for hepatocellular carcinoma

et al. 2019

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Late diagnosis for Hepatocellular Carcinoma (HCC) remains one of the leading causes for the high mortality rate. The apurinic/apyrimidinic endonuclease 1 (APE1), an essential member of the base excision DNA repair (BER) pathway, contributes to cell response to oxidative stress and has other non-repair activities. In this study, we evaluate the role of serum APE1 (sAPE1) as a new diagnostic biomarker and we investigate the biological role for extracellular APE1 in HCC. sAPE1 level was quantified in 99 HCC patients, 50 non-HCC cirrhotic and 100 healthy controls. The expression level was significantly high in HCC (75.8 [67.3–87.9] pg/mL) compared to cirrhosis (29.8 [18.3–36.5] pg/mL] and controls (10.8 [7.5–13.2] pg/mL) (p < 0.001). The sAPE1 level corresponded with its protein expression in HCC tissue. sAPE1 had high diagnostic accuracy to differentiate HCC from cirrhotic (AUC = 0.87, sensitivity 88%, specificity 71%, cut-off of 36.3 pg/mL) and healthy subjects (AUC 0.98, sensibility 98% and specificity 83%, cut-off of 19.0 pg/mL). Recombinant APE1, exogenously added to JHH6 cells, significantly promotes IL-6 and IL-8 expression, suggesting a role of sAPE1 as a paracrine pro-inflammatory molecule, which may modulate the inflammatory status in cancer microenvironment. We described herein, for the first time to our knowledge, that sAPE1 might be considered as a promising diagnostic biomarker for HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serum AP-endonuclease 1 (sAPE1) as novel biomarker for hepatocellular carcinoma

et al. 2019

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“…Nath and colleagues demonstrated that AP endonuclease is released as extracellular vesicles by monocytes in response to inflammation. Then, APE1 is associated with the cell surface of monocytes, increases the expression and secretion of IL-6, and modulates the inflammatory response [94]. Therefore, it was shown that subsequent production of IL-6 stimulates APE1 translocation from the nucleus to the cytoplasm and additionally increases AP endonuclease secretion [91,94].…”

Section: The Extracellular Role Of Ape1 In Regulating Ros Levels and mentioning

confidence: 99%

A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives

Betlej

Bator

Pyrkosz

et al. 2020

Genes

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Monocytes, which play a crucial role in the immune system, are characterized by an enormous sensitivity to oxidative stress. As they lack four key proteins responsible for DNA damage response (DDR) pathways, they are especially prone to reactive oxygen species (ROS) exposure leading to oxidative DNA lesions and, consequently, ROS-driven apoptosis. Although such a phenomenon is of important biological significance in the regulation of monocyte/macrophage/dendritic cells’ balance, it also a challenge for monocytic mechanisms that have to provide and maintain genetic stability of its own DNA. Interestingly, apurinic/apyrimidinic endonuclease 1 (APE1), which is one of the key proteins in two DDR mechanisms, base excision repair (BER) and non-homologous end joining (NHEJ) pathways, operates in monocytic cells, although both BER and NHEJ are impaired in these cells. Thus, on the one hand, APE1 endonucleolytic activity leads to enhanced levels of both single- and double-strand DNA breaks (SSDs and DSBs, respectively) in monocytic DNA that remain unrepaired because of the impaired BER and NHEJ. On the other hand, there is some experimental evidence suggesting that APE1 is a crucial player in monocytic genome maintenance and stability through different molecular mechanisms, including induction of cytoprotective and antioxidant genes. Here, the dual face of APE1 is discussed.

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“…In hyperacetylation condition, APE1/Ref-1 can be secreted from human embryonic kidney 293 (HEK293) cells [11] and vascular endothelial cells [16]. It also was proposed that APE1/Ref-1 is secreted from monocytes in response to lipopolysaccharide [17]. The ApoE knockout mouse (ApoE −/− ) model is widely used to investigate the pathogenesis of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Plasma APE1/Ref-1 Correlates with Atherosclerotic Inflammation in ApoE−/− Mice

et al. 2020

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Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is involved in DNA base repair and reducing activity. However, the role of APE1/Ref-1 in atherosclerosis is unclear. Herein, we investigated the role of APE1/Ref-1 in atherosclerotic apolipoprotein E (ApoE−/−) mice fed with a Western-type diet. We found that serologic APE1/Ref-1 was strongly correlated with vascular inflammation in these mice. Neutrophil/lymphocyte ratio (NLR), endothelial cell/macrophage activation, and atherosclerotic plaque formation, reflected by atherosclerotic inflammation, were increased in the ApoE−/− mice fed with a Western-type diet. APE1/Ref-1 expression was upregulated in aortic tissues of these mice, and was co-localized with cells positive for cluster of differentiation 31 (CD31) and galectin-3, suggesting endothelial cell/macrophage expression of APE1/Ref-1. Interestingly, APE1/Ref-1 plasma levels of ApoE−/− mice fed with a Western-type diet were significantly increased compared with those of the mice fed with normal diet (15.76 ± 3.19 ng/mL vs. 3.51 ± 0.50 ng/mL, p < 0.05), and were suppressed by atorvastatin administration. Correlation analysis showed high correlation between plasma APE1/Ref-1 levels and NLR, a marker of systemic inflammation. The cut-off value for APE1/Ref-1 for predicting atherosclerotic inflammation at 4.903 ng/mL showed sensitivity of 100% and specificity of 91%. We conclude that APE1/Ref-1 expression is upregulated in aortic endothelial cells/macrophages of atherosclerotic mice, and that plasma APE1/Ref-1 levels could predict atherosclerotic inflammation.

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The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression

Cited by 32 publications

References 65 publications

Serum AP-endonuclease 1 (sAPE1) as novel biomarker for hepatocellular carcinoma

Serum AP-endonuclease 1 (sAPE1) as novel biomarker for hepatocellular carcinoma

A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives

Plasma APE1/Ref-1 Correlates with Atherosclerotic Inflammation in ApoE−/− Mice

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