KDELC2 Upregulates Glioblastoma Angiogenesis via Reactive Oxygen Species Activation and Tumor-Associated Macrophage Proliferation

by Selleckchem | Jun 03 2023

Glioblastoma is notorious for its rapid progression and neovascularization. In this study, it was found that KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) stimulated vasculogenic factor expression and induced human umbilical vein endothelial cell (HUVEC) proliferation. The NLRP3 inflammasome and autophagy activation via hypoxic inducible factor 1 alpha (HIF-1α) and mitochondrial reactive oxygen species (ROS) production was also confirmed. The application of the NLRP3 inflammasome inhibitor MCC950 and autophagy inhibitor 3-methyladenine (3-MA) indicated that the above phenomenon activation correlated with an endothelial overgrowth. Furthermore, KDELC2 suppression decreased the endoplasmic reticulum (ER) stress factors' expression. The ER stress inhibitors, such as salubrinal and GSK2606414, significantly suppressed HUVEC proliferation, indicating that ER stress promotes glioblastoma vascularization. Finally, shKDELC2 glioblastoma-conditioned medium (CM) stimulated TAM polarization and induced THP-1 cells to transform into M1 macrophages. In contrast, THP-1 cells co-cultured with compensatory overexpressed (OE)-KDELC2 glioblastoma cells increased IL-10 secretion, a biomarker of M2 macrophages. HUVECs co-cultured with shKDELC2 glioblastoma-polarized THP-1 cells were less proliferative, demonstrating that KDELC2 promotes angiogenesis. Mito-TEMPO and MCC950 increased caspase-1p20 and IL-1β expression in THP-1 macrophages, indicating that mitochondrial ROS and autophagy could also interrupt THP-1-M1 macrophage polarization. In conclusion, mitochondrial ROS, ER stress, and the TAMs resulting from OE-KDELC2 glioblastoma cells play important roles in upregulating glioblastoma angiogenesis.

Comments：

This study suggests that KDEL containing 2 (KDELC2) stimulates vasculogenic factor expression and induces human umbilical vein endothelial cell (HUVEC) proliferation, leading to glioblastoma angiogenesis. The activation of the NLRP3 inflammasome and autophagy via hypoxic inducible factor 1 alpha (HIF-1α) and mitochondrial reactive oxygen species (ROS) production is confirmed to play a role in this phenomenon. The study also shows that the suppression of KDELC2 decreases the expression of endoplasmic reticulum (ER) stress factors, and ER stress inhibitors suppress HUVEC proliferation, indicating that ER stress promotes glioblastoma vascularization.

Furthermore, the study suggests that shKDELC2 glioblastoma-conditioned medium (CM) stimulates TAM polarization, which leads to THP-1 cells transforming into M1 macrophages. Conversely, THP-1 cells co-cultured with compensatory overexpressed (OE)-KDELC2 glioblastoma cells increase IL-10 secretion, a biomarker of M2 macrophages. HUVECs co-cultured with shKDELC2 glioblastoma-polarized THP-1 cells were less proliferative, demonstrating that KDELC2 promotes angiogenesis. Additionally, the study indicates that mitochondrial ROS, ER stress, and TAMs resulting from OE-KDELC2 glioblastoma cells play important roles in upregulating glioblastoma angiogenesis.

Overall, these findings suggest that KDELC2 plays a significant role in promoting glioblastoma angiogenesis through the activation of multiple pathways, including NLRP3 inflammasome, autophagy, ER stress, and TAM polarization. The study highlights the potential for targeting these pathways to inhibit glioblastoma growth and angiogenesis.