1. Academic Validation
  2. AMG232 inhibits the angiogenesis in glioma through p53/RBM4/VEGFR2 pathway

AMG232 inhibits the angiogenesis in glioma through p53/RBM4/VEGFR2 pathway

  • J Cell Sci. 2023 Jan 5;jcs.260270. doi: 10.1242/jcs.260270.
Yao Xiao 1 Mingliang Li 1 Teng Ma 1 Hao Ning 1 Libo Liu 1
Affiliations

Affiliation

  • 1 Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, People's Republic of China.
Abstract

AMG232 effectively inhibits cancers with wild-type p53 by reactivating p53, but whether it inhibits glioma angiogenesis remains unclear. This study confirmed AMG232 inhibited the proliferation of glioma endothelial cells (GECs) in a dose-dependent manner and inhibited the angiogenesis of GECs. p53 and RNA Binding Motif protein 4 (RBM4) were lowly expressed in GECs, while MDM2 and VEGFR2/KDR/Flk-1 were highly expressed. In vitro and in vivo experiments confirmed AMG232 up-regulated p53, RBM4 and down-regulated MDM2, VEGFR2/KDR/Flk-1 by blocking the MDM2-p53 interaction. Both p53 silencing and RMB4 silencing significantly up-regulated the expression of VEGFR2/KDR/Flk-1, promoted the proliferation, migration and tube formation of GECs, and reversed the effects of AMG232 on down-regulating VEGFR2/KDR/Flk-1 and inhibiting the angiogenesis of GECs. AMG232 increased RBM4 expression by up-regulating p53, and p53 bound to RBM4 and promoted its transcription. RBM4 bound to and shorten the half-life of VEGFR2/KDR/Flk-1, promoting its degradation. Finally, AGM232 resulted in a significant decrease in new vessels and hemoglobin content in vivo. This study proved AMG232 inhibited glioma angiogenesis by blocking the MDM2-p53 interaction, in which the p53/RBM4/VEGFR2/KDR/Flk-1 pathway played an important role.

Keywords

AMG232; Angiogenesis; Glioma; RBM4; VEGFR2; p53.

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