Apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) is essential for IL-21-induced signal transduction through ERK1/2 pathway

Juliana, Farha Matin; Nara, Hidetoshi; Onoda, Tadashi; Rahman, Mizanur; Araki, Akemi; Jin, Lianjin; Fujii, Hodaka; Tanaka, Nobuyuki; Hoshino, Tomoaki; Asao, Hironobu

doi:10.1016/j.bbrc.2012.03.051

Cited by 8 publications

(8 citation statements)

References 36 publications

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“…In this study, we measured pERK1/2 using human T cells and neutrophils in whole peripheral blood stimulated with various cytokines, such as IFN-α, interleukin (IL)-21, and G-CSF alone or in combination, to confirm the negative correlation. Although IFN-α and IL-21 primarily activate STAT3 pathways, these cytokines simultaneously activate the ERK pathway in various types of cells (Juliana et al, 2012;Zhao et al, 2015). G-CSF also primarily activates STAT3 and concomitantly activates the ERK pathway in myeloid cells (Kamezaki et al, 2005).…”

Section: Homeostatic Erk1/2 Pathway Is a Special Pattern Of Type 3 (Pmentioning

confidence: 99%

Five patterns of cell signaling pathways associated with cell behavior

Takeda

Kawano

et al. 2020

Preprint

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Cell signaling pathway is complex systems. Here, we present a concept for a new approach to analyze cell signaling pathway associated with cell behavior. In theoretically, cell behavior is recognized by energy and fluctuation. In this study, we measured phosphorylation level of signal transducers in a cell and fluctuation of the phosphorylation level in the cell population using flow cytometry. Flow cytometric data of mean fluorescence intensity (MFI) and coefficient variation (CV) were considered to the energy and the fluctuation, respectively. Topologically, the changes of MFI and CV were categorized into five patterns (we tentatively named as attractive, subsequent, passive, counter, and negative arbiter). In this study, we clarified the relationship between the cell behavior and the five patterns. Furthermore, combining the five patterns can define the signaling pathways, such as simple activated signal, oscillating signal, regulatory signal, robust signal, or homeostatic signal. These observations provide a proof of concept for general strategy to use the five patterns for connection between cell signaling pathway and cell behavior.

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Section: Homeostatic Erk1/2 Pathway Is a Special Pattern Of Type 3 (Pmentioning

confidence: 99%

Five patterns of cell signaling pathways associated with cell behavior

Takeda

Kawano

et al. 2020

Preprint

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“…The pivotal role of APE1 is demonstrated by its function in cellular viability and embryonic development [24], due to its role in DNA repair activity and other recently characterized non-canonical functions. In fact, APE1 also plays an important role as redox effector on many transcriptional factors, such as NF-κB, HIF-1α, STAT-3, PAX8, AP-1 and p53 [23][24][25][26][27], regulating important genes involved in tumor progression. Moreover, new interesting molecular functions involved in RNA metabolism were recently discovered in our laboratory [23], including processing of damaged RNA [28], miRNAs [29] and abasic and oxidized ribonucleotides embedded in DNA [30].…”

Section: Introductionmentioning

confidence: 99%

APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC

Malfatti

Gerratana

Dalla

et al. 2019

J Exp Clin Cancer Res

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Background Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors’ expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies. Methods We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels’ correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression. Results APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins. Conclusions APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches. Electronic supplementary material The online version of this article (10.1186/s13046-019-1294-9) contains supplementary material, which is available to authorized users.

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“…Ape1 is essential for specific cytokine-induced signal transduction, including that of interleukin-21 (1) and cluster of differentiation (CD)40L (2). CD40L triggers its receptor, CD40, which consequently mediates Ape1 nuclear translocation in human Burkitt’s lymphoma cells (2).…”

Section: Introductionmentioning

confidence: 99%

“…Embryos without Ape1 expression die in utero between implantation and day 6.5, indicating normal embryonic development requires Ape1 (4). This gene is aberrant in various cancer cells (1). Our previous study demonstrated the aberrant expression of Ape1 in pancreatic cancer (5) and its role in tumor angiogenesis (6)…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression of redox protein Ape1 in colon cancer stem cells

et al. 2014

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Ape1 is an important redox protein, essential for specific cytokine-induced signal transduction. Ape1 signaling is also important in regulating the growth of cancer cells, including colon cancer cells. The present study investigated whether Ape1 signaling plays a role in the regulation of colon cancer stem cell (CCSC) growth. The results showed that Ape1 was aberrantly expressed in CCSCs, as determined by quantitative (q)PCR assay. A laser confocal microscopy assay demonstrated that the Ape1 protein was mainly distributed in the nuclei, but not the cytoplasm, of the CSCs. Treatment of CCSCs with Ape1 redox inhibitor (E3330) significantly affected growth in vitro. In colon cancer xenograft mice, in vivo administration of E3330 enhanced tumor responses to the chemotherapeutic drug, 5-fluorouracil (5-FU). Furthermore, the combination of E3330 and 5-FU evidently increased the cytotoxicity of 5-FU in CSC growth. In the qPCR assay, the CCSCs were demonstrated to express the dominant ATP-binding cassette sub-family G member 2 (ABC-G2), but not the multidrug resistance 1, genes. Thus, we hypothesized that drug resistance in CCSCs is mediated by ABC-G2. Since CSCs are involved in cancer metastasis, the Ape1 inhibitor may be a potential agent in the inhibition of colon cancer growth and metastasis.

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Apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) is essential for IL-21-induced signal transduction through ERK1/2 pathway

Cited by 8 publications

References 36 publications

Five patterns of cell signaling pathways associated with cell behavior

Five patterns of cell signaling pathways associated with cell behavior

APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC

Aberrant expression of redox protein Ape1 in colon cancer stem cells

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