title: Autophagy mediates paracrine regulation of vascular endothelial cells.
abstract: 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.
authors.affiliation: Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kwang Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Pritha
authors.initials: P
authors.lastname: Paul
authors.forename: Jingbo
authors.initials: J
authors.lastname: Qiao
authors.forename: Dai H
authors.initials: DH
authors.lastname: Chung
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D049109:Cell Proliferation; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000254:growth & development; D019886:Gastrin-Releasing Peptide / Q000502:physiology*; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D019886:Gastrin-Releasing Peptide; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C502778:ATG5 protein, human; C491997:BECN1 protein, human; C546842:MTOR protein, human