Histone deacetylases inhibitor trichostatin A modulates the extracellular release of APE1/Ref-1

Choi, Sunga; Lee, Yu Ran; Park, Myoung Soo; Joo, Hee Kyoung; Cho, Eun Jung; Kim, Hyo Shin; Kim, Cuk-Seong; Park, Jin Bong; Irani, Kaikobad; Jeon, Byeong Hwa

doi:10.1016/j.bbrc.2013.04.101

Cited by 39 publications

(64 citation statements)

References 24 publications

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“…However, APE1 is not a typical secretory protein as it lacks classic secretory signals based on protein sequence analysis. Intriguingly, there are reports showing that APE1 is secreted under specific stimuli [22, 23]. The secretion of APE1 was associated with its cytoplasmic translocation according to these reports; however, we failed to build a positive connection between sAPE1 and its cytoplasmic distribution.…”

Section: Discussioncontrasting

confidence: 55%

Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients

Zhang

Dai

et al. 2016

Oncotarget

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PurposeTo define the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in predicting the prognosis and chemotherapeutic response of non-small cell lung cancer patients receiving platinum-containing chemotherapy.ResultsOur investigations found that serum APE1 level was significantly elevated in 229 of 412 NSCLC patients and correlated with its level in tissue (r2 = 0.639, p < 0.001). The elevated APE1 level in both tissue and serum of patients prior to chemotherapy was associated with worse progression-free survival (HR: 2.165, p < 0.001, HR: 1.421, p = 0.012), but not with overall survival. After 6 cycles of chemotherapy, a low APE1 serum level was associated with better overall survival (HR: 0.497, p = 0.010).Experimental DesignWe measured APE1 protein levels in biopsy tissue from 172 NSCLC patients and sera of 412 NSCLC patients receiving platinum-based chemotherapy by immunohistochemistry and a newly established sensitive and specific enzyme-linked immunosorbent assay, respectively. APE1 levels in sera of 523 healthy donors were also determined as control.ConclusionsOur studies indicate that APE1 is a biomarker for predicting prognosis and therapeutic efficacy in NSCLC. The chemotherapy-naïve serum APE1 level, which correlated with its tissue level inversely associated with progression-free survival of platinum-containing doublet chemotherapy, whereas post-treatment serum APE1 level was inversely associated with overall survival.

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Section: Discussioncontrasting

confidence: 55%

Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients

Zhang

Dai

et al. 2016

Oncotarget

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“…While recent evidences indicate that APE1 can be secreted into the plasma [6, 7], the physiological or pathological role of extracellular APE1 has not been documented yet. In this study, for the first time, we show that the oxidative DNA damage repair protein APE1 can be actively released from monocytes upon inflammatory challenges.…”

Section: Discussionmentioning

confidence: 99%

“…Precipitation of extracellular proteins from cell culture supernatants was done as described previously [6]. …”

Section: Methodsmentioning

confidence: 99%

“…Subsequently, an extra-nuclear role of the cytoplasmic APE1 in regulating oxidative stress and inflammatory responses was also reported [5]. Interestingly, a recent report demonstrated the secretion of APE1 into the extracellular medium in cultured HEK293 and tumor cells [6]. Concurrently, another report identified the presence of plasma APE1 in lipopolysaccharide (LPS)-induced endotoxemic rats [7].…”

Section: Introductionmentioning

confidence: 99%

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

Nath

Roychoudhury

Kling

et al. 2017

Cellular Signalling

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The human apurinic/apyrimidinic endonuclease 1 (APE1) is a pleiotropic nuclear protein with roles in DNA base excision repair pathway as well as in regulation of transcription. Recently, the presence of extracellular plasma APE1 was reported in endotoxemic rats. However, the biological significance and the extracellular function of APE1 remain unclear. In this study, we found that monocytes secrete APE1 upon inflammatory challenges. Challenging the monocytic cells with extracellular APE1 resulted in the increased expression and secretion of the pro-inflammatory cytokine IL-6. Additionally, the extracellular APE1 treatment activated the transcription factor NF-κB, followed by its increased occupancy at the IL-6 promoter, resulting in the induction of IL-6 expression. APE1-induced IL-6 further served to elicit autocrine and paracrine cellular responses. Moreover, the extracellular IL-6 promoted the secretion of APE1, thus indicating a functional feedforward loop in this pathway. Furthermore, we show that APE1 is secreted through extracellular vesicles formation via endosomal sorting complex required for transport (ESCRT)-dependent pathway. Together, our study demonstrates a novel role of extracellular APE1 in IL-6-dependent cellular responses.

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“…[16][17][18][19][20][21][22] It has been recently found that APE1 acetylation promotes its own extracellular secretion 23 and may trigger apoptosis of cancer cells via RAGE binding. 24 In particular, APE1 K6/K7 may undergo acetylation during cell response to genotoxic insults, and the acetylation status of these lysines, controlled by the sirtuin 1 (SIRT1) deacetylase activity, is important in modulating protein DNA-repair functions by regulating the kinetics of its interaction with other enzymes involved in base excision repair.…”

Section: Introductionmentioning

confidence: 99%

Monoclonal antibodies against pools of mono- and polyacetylated peptides selectively recognize acetylated lysines within the context of the original antigen

Sandomenico

Focà

Sanguigno

et al. 2016

mAbs

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Post-translational modifications (PTMs) strongly influence the structure and function of proteins. Lysine side chain acetylation is one of the most widespread PTMs, and it plays a major role in several physiological and pathological mechanisms. Protein acetylation may be detected by mass spectrometry (MS), but the use of monoclonal antibodies (mAbs) is a useful and cheaper option. Here, we explored the feasibility of generating mAbs against single or multiple acetylations within the context of a specific sequence. As a model, we used the unstructured N-terminal domain of APE1, which is acetylated on Lys27, Lys31, Lys32 and Lys35. As immunogen, we used a peptide mixture containing all combinations of single or multi-acetylated variants encompassing the 24-39 protein region. Targeted screening of the resulting clones yielded mAbs that bind with high affinity to only the acetylated APE1 peptides and the acetylated protein. No binding was seen with the non-acetylated variant or unrelated acetylated peptides and proteins, suggesting a high specificity for the APE1 acetylated molecules. MAbs could not finely discriminate between the differently acetylated variants; however, they specifically bound the acetylated protein in mammalian cell extracts and in intact cells and tissue slices from both breast cancers and from a patient affected by idiopathic dilated cardiomyopathy. The data suggest that our approach is a rapid and cost-effective method to generate mAbs against specific proteins modified by multiple acetylations or other PTMs.

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Histone deacetylases inhibitor trichostatin A modulates the extracellular release of APE1/Ref-1

Cited by 39 publications

References 24 publications

Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients

Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients

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

Monoclonal antibodies against pools of mono- and polyacetylated peptides selectively recognize acetylated lysines within the context of the original antigen

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