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Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with

Mengqi Jia1, Yanxia Guo1, Deyu Zhu1

  • 1Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|February 8, 2018
PubMed

Insights

Anterior gradient 2 (AGR2) promotes aggressive prostate cancer by enhancing blood vessel formation and metastasis. Blocking AGR2

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Anterior gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) linked to cancer progression.
  • High AGR2 levels correlate with aggressive phenotypes in prostate cancer (PCa).

Purpose of the Study:

  • To investigate the role of AGR2 in promoting prostate cancer aggressiveness and metastasis.
  • To elucidate the mechanisms by which AGR2 influences angiogenesis and epithelial-mesenchymal transition (EMT).

Main Methods:

  • Utilized patient-derived xenografts and surgical intra-prostate implantation of PCa cells in mouse models.
  • Analyzed angiogenesis (VEGFR2, CD34) and invasion (Vimentin) markers in tumor and metastatic tissues.
  • Investigated the interaction between recombinant human AGR2 (rhAGR2) and rhVEGFA using biochemical assays.
  • Assessed the impact of AGR2 on p65 protein stability, NF-κB activation, and EMT.
  • Evaluated the efficacy of GSH and cabozantinib in blocking AGR2's pro-angiogenic effects in vitro and in vivo.

Main Results:

  • High AGR2 levels promoted aggressive PCa phenotypes and increased blood vessel density in tumors.
  • Secreted AGR2 physically interacted with VEGFA via a disulfide bond, enhancing VEGFR2 activity and promoting angiogenesis.
  • Cytosolic AGR2 stabilized p65, activating NF-κB and facilitating EMT.
  • GSH and cabozantinib effectively inhibited rhAGR2's pro-angiogenic effects, while bevacizumab did not.

Conclusions:

  • AGR2 drives prostate cancer progression through both secreted and cytosolic mechanisms, impacting angiogenesis and metastasis.
  • Secreted AGR2 may serve as a predictive biomarker for selecting effective angiogenesis-targeting therapies like cabozantinib.
  • Targeting AGR2 or its downstream pathways presents a potential therapeutic strategy for aggressive prostate cancer.
Keywords:
AGR2AngiogenesisInvasion and metastasisProstate cancerVEGFA

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