GSE157779
Targeting of glioma stem-like cells with a parthenolide derivative ACT001 through inhibition of AEBP1/PI3K/AKT signaling
Glioblastoma (GBM) is the most lethal primary brain tumor in adults with a median survival of around 15 months. A potential treatment strategy involves targeting glioma stem-like cells (GSCs) that are able to initiate, maintain, and repopulate the tumor mass. Here, we identify ACT001, a parthenolide derivative, targeting GSCs through regulation of adipocyte enhancer binding protein 1 (AEBP1) signaling.GSCs exhibit high response to ACT001 in compared with normal human astrocytes. AEBP1 is a putative target of ACT001 by RNA-Seq analysis, which expression associates with prognosis of GBM patients. Knockdown of AEBP1 inhibits GSC proliferation whereas ectopic expression of AEBP1 increases GSC proliferation and xenograft tumor growth. AEBP1 overexpression also attenuates ATC001-inhibited GSC orthotopic xenograft tumor growth. Treatment with ACT001 or PI3K inhibitor or AEBP1 depletion decreases AKT phosphorylation and GSC proliferation. However, constitutive AKT activation rescues ACT001 treatment or AEBP1 knockdown-inhibited cell proliferation. Additionally, ACT001 blocks TGF-ß-activated AEBP1/AKT signaling in GSCs. ACT001 exhibits antitumor activity either as a single agent or in combination with SHP099, which provides significant survival benefits for GSC xenograft tumor -bearing animals. Overall design: Examination of differential gene expression in GSC 83 cells treated with or without ACT001 .