Autophagy mediates paracrine regulation of vascular endothelial cells.

Kim KW, Paul P, Qiao J, Chung DH
Lab Invest. 2013 93 (6): 639-45

PMID: 23608754 · PMCID: PMC3669233 · DOI:10.1038/labinvest.2013.57

Gastrin-releasing peptide (GRP) is a proangiogenic ligand secreted by tumors and acts directly upon binding to GRP receptor in endothelial cells. Angiogenesis plays a critical role in the pathology of various diseases, including cancer, as the formation of new blood vessels potentiates the rate of tumor growth and dissemination. GRP increases the migration of endothelial cells, but much is unknown about its role on endothelial cell proliferation and survival, as well as the signaling pathways involved. In the present study, we showed that GRP increases endothelial cell proliferation and tubule formation. There was a time-dependent increase in the levels of phosphorylated AKT, mammalian target of rapamycin (mTOR), and S6R in human umbilical vein endothelial cells treated with GRP. Interestingly, GRP treatment decreased the expression of proautophagic factors, ATG5, BECN1, and LC3 proteins. GRP also attenuated rapamycin-induced formation of autophagosomes. Moreover, overexpression of ATG5 or BECN1 significantly decreased tubule formation induced by exogenous GRP, whereas siRNA against ATG5 or BECN1 resulted in increased tubule formation with GRP treatment. Our results show that GRP inhibits the process of autophagy in vascular endothelial cells, thereby increasing endothelial cell proliferation and tubule formation. Here, we describe a novel role of GRP in the regulation of autophagy of endothelial cells, thereby providing a potential new therapeutic strategy in targeting angiogenesis during cancer progression.

MeSH Terms (20)

Apoptosis Regulatory Proteins Autophagy Autophagy-Related Protein 5 Beclin-1 Cell Proliferation Coculture Techniques Endothelial Cells Endothelium, Vascular Gastrin-Releasing Peptide Gene Expression Regulation Humans Human Umbilical Vein Endothelial Cells Membrane Proteins Microtubule-Associated Proteins Neovascularization, Pathologic Paracrine Communication Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt Signal Transduction TOR Serine-Threonine Kinases

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