Abstract
The limitation of targeting VEGF/VEGFR2 signalling to stop angiogenesis in cancer therapy has been blamed on re-activation of alternative receptor tyrosine kinases by compensatory angiogenic factors. Targeting MAPK and PI3K signaling pathways in endothelial cells may be an alternative or complementary approach. Herein we aimed to evaluate the antitumor and antiangiogenic potential of a novel pyrazolyl-urea kinase inhibitor, GeGe3, and to identify its kinase targets.We found GeGe3 to inhibit the proliferation of HUVEC and endothelial tube formation. GeGe3 impaired inter-segmental angiogenesis during development of zebrafish embryos. In mice, GeGe3 blocked angiogenesis and tumor growth in transplanted subcutaneous Lewis Lung Carcinomas. Screening for GeGe3-targeted kinases revealed Aurora B, Aurora C, NEK10, polo-like kinase (PLK)2, PLK3, DMPK1 and CAMK1 as candidate targets. Biochemical analysis of these kinases showed DMPK1 regulation upon VEGF challenge. Investigation of the role of DMPK1 in endothelial cells revealed DMPK1 as a novel mediator of angiogenesis that controls the activation of MAPK signaling, proliferation and migration. GeGe3 alters angiogenesis by targeting DMPK in tumor endothelial cells and pericytes.The pyrazolyl-urea GeGe3, a novel blocker of MAPK and PI3K pathways, strongly inhibits physiological and tumor angiogenesis. We also report GeGe3-targeted kinase DMPK as a novel mediator of angiogenesis.
Highlights
Angiogenesis, the formation of new blood vessels from existing vasculature, is indispensable for tumor growth and expansion beyond 2-mm3 in volume [1]
We recently demonstrated that Vascular Endothelial Growth Factor (VEGF)-induced human umbilical vein endothelial cells (HUVECs) migration was inhibited by ethyl 1-(2-hydroxypentyl)-5-(3(3-(trifluoromethyl)phenyl)ureido)-1H-pyrazole-4carboxylate (GeGe3), a pyrazolylurea compound that we found to block the activation of mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways in HUVEC [37]
Given the role of MAPK and PI3K signaling pathways in endothelial cell proliferation, our results suggested a potential capacity of GeGe3 to interfere with endothelial cell proliferation
Summary
Angiogenesis, the formation of new blood vessels from existing vasculature, is indispensable for tumor growth and expansion beyond 2-mm in volume [1]. Tumor angiogenesis depends on angiogenic factors and the transduction of their signals in endothelial cells [2]. Extensive expression of Vascular Endothelial Growth Factor (VEGF)-A during tumor growth was reported for several tumor types [3, 4]. VEGF-A is the major angiogenic factor that activates VEGF receptors (VEGFR)-1 and -2 on endothelial cells. VEGFR activation triggers angiogenic migration, proliferation and survival of endothelial cells. VEGF, with humanized neutralizing monoclonal antibody, or the receptors with receptor tyrosine kinase inhibitors, are promising cancer therapy approaches [5,6,7,8]. Tumors express compensatory angiogenic factors to overcome VEGF blockade, which frequently leads to rebound in tumor angiogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
