ATRX-dependent SVCT2 mediates macrophage infiltration in the glioblastoma xenograft model

• Published in: Journal of neurophysiology Vol. 127; no. 5; pp. 1309 - 1316
• Main Authors: Shang, Jinxing, Wang, Yana, Li, Zhuangzhuang, Jiang, Lijun, Bai, Qingling, Zhang, Xiaoling, Xiao, Guoxin, Zhang, Jinguo
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• Subjects: alpha-Thalassemia; Animals; Ascorbic Acid; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Disease Models, Animal; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Heterografts; Humans; Macrophages - metabolism; Macrophages - pathology; Mental Retardation, X-Linked; Sodium - metabolism; Sodium-Coupled Vitamin C Transporters; Symporters; X-linked Nuclear Protein - genetics; X-linked Nuclear Protein - metabolism; Ccl2; GBM; ATRX; Ccl4; SVCT2
• ISSN: 0022-3077; 1522-1598; 1522-1598
• DOI: 10.1152/jn.00486.2021

This study demonstrates that interference of ATRX-dependent SVCT2-mediated chemokine-induced macrophage infiltration could inhibit tumor cell proliferation in the GBM cell line-derived xenograft model. ATRX and SVCT2 are potential treatment targets identified in this study. The α thalassemia/mental retardation syndrome X-linked (ATRX) mutation impairs DNA damage repair in glioblastoma (GBM), making these cells more susceptible to treatment, which may contribute to the survival advantage in patients with GBM containing ATRX mutations. To better understand the role of ATRX in GBM, genes correlated with ATRX expression were screened in the Cancer Genome Atlas (702 cases) and Chinese Glioma Genome Atlas (325 cases) databases. Sodium-vitamin C cotransporter 2 (SVCT2) was the most positively correlated gene with ATRX expression. ATRX (about 1.99-fold) and SVCT2 (about 2.25-fold) were upregulated in GBM tissues from 40 patients compared with normal brain tissues from 23 subjects. ShSVCT2 transfection did not alter the in vitro viability of GL261 cells. At the same time, it could inhibit the proliferation of GL261 cells in the orthotopic transplantation model with diminished infiltrating macrophages (CD45 high CD11b + ), downregulated chemokine (C-C motif) ligand 2 (Ccl2), Ccl4, C-X-C motif chemokine ligand 1 (Cxcl1), and Cxcl15 expression, and decreased p-IκBα and p-c-Jun expression. Effect of ShSVCT2 transfection could be reversed by overexpression of SVCT2. siRNA interference of ATRX-dependent SVCT2 signal with shSVCT2 could inhibit tumor cell proliferation in Glu261-LuNeo xenograft tumor model with more survival advantage, probably by the inhibited macrophage chemotaxis. These results indicate that ATRX-dependent SVCT2-mediated chemokine-induced macrophage infiltration is regulated by the NF-κB pathway, which could be considered as treatment targets. NEW & NOTEWORTHY This study demonstrates that interference of ATRX-dependent SVCT2-mediated chemokine-induced macrophage infiltration could inhibit tumor cell proliferation in the GBM cell line-derived xenograft model. ATRX and SVCT2 are potential treatment targets identified in this study.