Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway

Jia, Mengqi; Guo, Yanxia; Zhu, Deyu; Zhang, Nianzhao; Lin, Li; Jiang, Jin; Dong, Yaru; Xu, Qingqing; Zhang, Xiulei; Wang, Meijuan; Yu, Hong; Wang, Fang; Tian, Keli; Zhang, Jin‐San; Young, Charles Y.F.; Lou, Hongxiang; Yuan, Huiqing

doi:10.1016/j.bbadis.2018.01.021

Cited by 34 publications

(36 citation statements)

References 25 publications

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“…Later, it was found that such a member of the protein disulfide isomerase family as P4HB is overexpressed in hepatocellular carcinoma cells and promotes EMT in them [227]. The elevated level of another protein disulfide isomerase, anterior gradient 2 (AGR2), was shown to drive EMT in prostate cancer, which was accompanied by the formation of the aggressive tumor cell phenotype with increased invasive, pro-metastatic, and angiogenic potentials [265]. The EMT-stimulating effect of AGR2 in prostate cancer cells was explained by AGR2-conferred stabilization of protein p65, which, as a result, was able to activate NFκB, thereby promoting EMT [265].…”

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

“…The elevated level of another protein disulfide isomerase, anterior gradient 2 (AGR2), was shown to drive EMT in prostate cancer, which was accompanied by the formation of the aggressive tumor cell phenotype with increased invasive, pro-metastatic, and angiogenic potentials [265]. The EMT-stimulating effect of AGR2 in prostate cancer cells was explained by AGR2-conferred stabilization of protein p65, which, as a result, was able to activate NFκB, thereby promoting EMT [265]. In addition, AGR2 appears to be one of the key players in forming the tumor niche and remodeling the tumor microenvironment to promote malignant growth with metastasis spread [266].…”

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

“…Extracellular (secreted) protein disulfide isomerases may also promote the stemness-associated activities of cancer cells. In the case of prostate cancer, secreted AGR2 was shown to stimulate angiogenesis by enhancing VEGF receptor 2 activity and facilitate metastasis spread [265]. In turn, extracellular AGR3 participates in the regulation of the adhesion and migration of breast cancer cells via activation of Src kinase-driven signaling [271].…”

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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“…Recently, eAGR2 was shown to be vascular endothelial growth factor receptor 2 (VEGFR2) stimulator in tumour progression by promoting angiogenesis [Jia et al., ]. Mechanistically, eAGR2 directly interacted with Vascular endothelial growth factor A, resulting in enhancement of Vascular endothelial growth factor (VEGF)/VEGFR2 signalling to promote angiogenesis.…”

Section: Agr2 and The Tnsmentioning

confidence: 99%

“…This activity can be blocked, at least partially, by a monoclonal antibody targeting the self‐dimerisation region in vitro and in vivo , suggesting that eAGR2 is a potential anti‐tumour target, which influences the activities of multiple extracellular signalling molecules. iAGR2 was shown to stabilise p65 [Jia et al., ], which in turn transcriptionally regulates EMT gene patterns and plays a critical role in inducing an AGR2‐facilitated aggressive phenotype. This AGR2 effect significantly blocked the antitumour activity of bevacizumab but not cabozantinib, providing evidence for anti‐angiogenic agents in cancer therapy.…”

Section: Agr2 and The Tnsmentioning

confidence: 99%

The role of protein disulphide isomerase AGR2 in the tumour niche

Delom

Nazaraliyev

Fessart

2018

Biology of the Cell

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In recent years, the discovery of 'tumour niche', a microenvironment that favours tumour development has changed our perspective of cancer. This microenvironment generated by the tumour cells itself and surrounding cells is capable of providing essential elements for its growth. Consequently, the homoeostasis of the secretory pathway (SP) has become an essential player in cancer development. The SP not only promotes cellular adaptation to protein misfolding due to oncogenic transformation or challenging tumour niche but also allows tumour cells to produce specific secretomes. This impacts tumour cells in cis-or trans-as well as stromal cells in the tumour niche. In this context, the Anterior GRadient 2 (AGR2) protein has been identified as a key player. AGR2 is a protein disulphide isomerase that resides in the endoplasmic reticulum (ER) and mediates the formation of disulphide bonds, catalyses the cysteine-based redox reactions and assists the quality control of proteins. AGR2 not only plays an essential role in the homoeostasis of the SP but also exerts pro-oncogenic gain-of-function due to its reported mislocalisation in the tumour niche microenvironment. In this review, we summarise the dual role of AGR2, inside and outside the ER, on the tumour niche and its microenvironment.

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Interferon‐regulatory factor‐1 boosts bevacizumab cardiotoxicity by the vascular endothelial growth factor A/14‐3‐3γ axis

Chen,

Xie,

Huang

et al. 2024

ESC Heart Failure

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AimMyocardial injury is a significant cause of death. This study investigated the role and underlying mechanism of interferon‐regulatory factor‐1 (IRF1) in bevacizumab (BVZ)‐induced cardiomyocyte injury.Methods and resultsHL‐1 cells and C57BL/6 mice receiving BVZ treatment were used to establish in vitro and in vivo models of myocardial injury. The relationship between VEGFA and 14‐3‐3γ was verified through co‐immunoprecipitation and Glutathione S Transferase (GST) pull‐down assay. Cell viability and apoptosis were analysed by MTT, propidium iodide (PI) staining and flow cytometry. The release of lactate dehydrogenase (LDH), cardiac troponins T (cTnT), and creatine kinase MB (CK‐MB) was measured using the enzyme linked immunosorbent assay. The effects of knocking down IRF1 on BVZ‐induced mice were analysed in vivo. IRF1 levels were increased in BVZ‐treated HL‐1 cells. BVZ treatment induced apoptosis, inhibited cell viability, and promoted the release of LDH, cTnT, and CK‐MB. IRF1 silencing suppressed BVZ‐induced myocardial injury, whereas IRF1 overexpression had the opposite effect. IRF1 regulated VEGFA expression by binding to its promoter, with the depletion of VEGFA or 14‐3‐3γ reversing the effects of IRF1 knockdown on the cell viability and apoptosis of BVZ‐treated HL‐1 cells. 14‐3‐3γ overexpression promoted cell proliferation, inhibited apoptosis, and reduced the release of LDH, cTnT, and CK‐MB, thereby alleviating BVZ‐induced HL‐1 cell damage. In vivo, IRF1 silencing alleviated BVZ‐induced cardiomyocyte injury by regulating the VEGFA/14‐3‐3γ axis.ConclusionThe IRF1‐mediated VEGFA/14‐3‐3γ signalling pathway promotes BVZ‐induced myocardial injury. Our study provides evidence for potentially new target genes for the treatment of myocardial injury.

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Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway

Cited by 34 publications

References 25 publications

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

The role of protein disulphide isomerase AGR2 in the tumour niche

Interferon‐regulatory factor‐1 boosts bevacizumab cardiotoxicity by the vascular endothelial growth factor A/14‐3‐3γ axis

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