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

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1864; no. 5; pp. 1622 - 1633
• Main Authors: Jia, Mengqi, Guo, Yanxia, Zhu, Deyu, Zhang, Nianzhao, Li, Lin, Jiang, Jin, Dong, Yiwen, Xu, Qingqing, Zhang, Xiulei, Wang, Meijuan, Yu, Haina, Wang, Fang, Tian, Keli, Zhang, Jinsan, Young, Charles Y.F., Lou, Hongxiang, Yuan, Huiqing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-05-2018
• Subjects: AGR2; Angiogenesis; Animals; Bevacizumab - pharmacology; Cell Line, Tumor; Humans; Invasion and metastasis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins - genetics; Proteins - metabolism; Proteins - pharmacology; Signal Transduction - drug effects; Signal Transduction - genetics; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; VEGFA; AGR2; Angiogenesis; Prostate cancer; Invasion and metastasis; VEGFA
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2018.01.021

Anterior gradient 2 (AGR2), an endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI), is associated with cancer development and malignant progression. Here, we show that high level of AGR2 promotes the aggressive phenotype of prostate cancer (PCa) mouse models developed by either patient-derived xenografts or surgical intra-prostate implantation of PCa cells, associated with enrichment of the blood vessel network in tumor tissues. Angiogenesis markers VEGFR2 and CD34, accompanied with the invasive marker Vimentin, were predominantly stained in metastatic liver tissues. Secreted AGR2 was defined to enhance VEGFR2 activity as evidenced by physical interaction of purified recombinant human AGR2 (rhAGR2) with rhVEGFA through the formation of a disulfide bond. Mutant or deleted thioredoxin motif in rhAGR2 was also unable to bind to rhVEGFA that led to the significant abolishment in the vessel formation, but partially affecting the aggressive process, implicating alternative mechanisms are required for AGR2-conferring metastasis. Cytosolic AGR2 contributed to cell metastasis ascribed to its stabilizing effect on p65 protein, which subsequently activated the NF-κB and facilitated epithelial to mesenchymal transition (EMT). Importantly, GSH and cabozantinib, but not bevacizumab, effectively blocked the pro-angiogenic effect of rhAGR2 in vitro and in vivo, providing evidence that secreted AGR2 acts as a predictive biomarker for selection of angiogenesis-targeting therapeutic drugs based on its levels in the circular system.
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•Secreted AGR2 directly interacts with VEGFA via the formation of disulfide bond, leading to the enhancement of angiogenesis.•Cytosolic AGR2 could stabilize p65 protein resulting in induction of EMT in prostate cancer cells.•Extracellular AGR2 impairs bevacizumab, but not cabozantinib, anti-angiogenesis and anti-tumor efficiency.