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MICAL2 is expressed in cancer associated neo-angiogenic capillary endothelia and it is required for endothelial cell viability, motility and VEGF response.

Abstract
The capacity of inducing angiogenesis is a recognized hallmark of cancer cells. The cancer microenvironment, characterized by hypoxia and inflammatory signals, promotes proliferation, migration and activation of quiescent endothelial cells (EC) from surrounding vascular network. Current anti-angiogenic drugs present side effects, temporary efficacy, and issues of primary resistance, thereby calling for the identification of new therapeutic targets. MICALs are a unique family of redox enzymes that destabilize F-actin in cytoskeletal dynamics. MICAL2 mediates Semaphorin3A-NRP2 response to VEGFR1 in rat ECs. MICAL2 also enters the p130Cas interactome in response to VEGF in HUVEC. Previously, we showed that MICAL2 is overexpressed in metastatic cancer. A small-molecule inhibitor of MICAL2 exists (CCG-1423). Here we report that 1) MICAL2 is expressed in neo-angiogenic ECs in human solid tumors (kidney and breast carcinoma, glioblastoma and cardiac myxoma, n = 67, were analyzed with immunohistochemistry) and in animal models of ischemia/inflammation neo-angiogenesis, but not in normal capillary bed; 2) MICAL2 protein pharmacological inhibition (CCG-1423) or gene KD reduce EC viability and functional performance; 3) MICAL2 KD disables ECs response to VEGF in vitro. Whole-genome gene expression profiling reveals MICAL2 involvement in angiogenesis and vascular development pathways. Based on these results, we propose that MICAL2 expression in ECs participates to inflammation-induced neo-angiogenesis and that MICAL2 inhibition should be tested in cancer- and noncancer-associated neo-angiogenesis, where chronic inflammation represents a relevant pathophysiological mechanism.
AuthorsIvana Barravecchia, Sara Mariotti, Angela Pucci, Francesca Scebba, Chiara De Cesari, Silvio Bicciato, Enrico Tagliafico, Elena Tenedini, Carla Vindigni, Marco Cecchini, Gabriele Berti, Marianna Vitiello, Laura Poliseno, Chiara Maria Mazzanti, Debora Angeloni
JournalBiochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1865 Issue 9 Pg. 2111-2124 (09 01 2019) ISSN: 1879-260X [Electronic] Netherlands
PMID31004710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 Elsevier B.V. All rights reserved.
Chemical References
  • Anilides
  • Benzamides
  • CCG 1423
  • Microfilament Proteins
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • MICAL2 protein, human
  • Oxidoreductases
Topics
  • Anilides (pharmacology)
  • Animals
  • Benzamides (pharmacology)
  • Blood Vessels (metabolism, pathology)
  • Cell Movement (drug effects)
  • Cell Proliferation
  • Cell Survival (drug effects)
  • Endothelial Cells (cytology, metabolism)
  • Gene Expression
  • Humans
  • Male
  • Microfilament Proteins (antagonists & inhibitors, genetics, metabolism)
  • Myocytes, Cardiac (cytology, metabolism)
  • Neoplasms (blood supply, pathology)
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic
  • Oxidoreductases (antagonists & inhibitors, genetics, metabolism)
  • RNA Interference
  • RNA, Small Interfering (metabolism)
  • Rats
  • Rats, Wistar
  • Vascular Endothelial Growth Factor A (metabolism)

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