ANGPTL4 Induces TMZ Resistance of Glioblastoma by Promoting Cancer Stemness Enrichment via the EGFR/AKT/4E-BP1 Cascade

International Journal of Molecular Sciences

卷:20

An-Chih Wu¹  Wen-Chang Chang¹  Yu-Ting Tsai¹  Wen-Bin Yang¹  Tsung-I. Hsu²  Tzu-Jen Kao²  Jian-Ying Chuang² 

[1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;

[2] Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan;

关键词: glioblastoma;    angiopoietin-like 4;    glioma stem-like cells;   

DOI  :  10.3390/ijms20225625

来源: DOAJ

【 摘 要 】

Glioblastoma (GBM) is the most aggressive type of brain tumor, with strong invasiveness and a high tolerance to chemotherapy. Despite the current standard treatment combining temozolomide (TMZ) and radiotherapy, glioblastoma can be incurable due to drug resistance. The existence of glioma stem-like cells (GSCs) is considered the major reason for drug resistance. However, the mechanism of GSC enrichment remains unclear. Herein, we found that the expression and secretion of angiopoietin-like 4 protein (ANGPTL4) were clearly increased in GSCs. The overexpression of ANGPTL4 induced GSC enrichment that was characterized by polycomb complex protein BMI-1 and SRY (sex determining region Y)-box 2 (SOX2) expression, resulting in TMZ resistance in GBM. Furthermore, epidermal growth factor receptor (EGFR) phosphorylation induced 4E-BP1 phosphorylation that was required for ANGPTL4-induced GSC enrichment. In particular, ANGPTL4 induced 4E-BP1 phosphorylation by activating phosphoinositide 3-kinase (PI3K)/AKT and extracellular signal−regulated kinase (ERK) cascades for inducing stemness. To elucidate the mechanism contributing to ANGPTL4 upregulation in GSCs, chromatin immunoprecipitation coupled with sequencing (ChIP-Seq) revealed that specificity protein 4 (Sp4) was associated with the promoter region, −979 to −606, and the luciferase reporter assay revealed that Sp4 positively regulated activity of the ANGPTL4 promoter. Moreover, both ANGPTL4 and Sp4 were highly expressed in GBM and resulted in a poor prognosis. Taken together, Sp4-mediated ANGPTL4 upregulation induces GSC enrichment through the EGFR/AKT/4E-BP1 cascade.

【 授权许可】

Unknown