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Azathioprine Blocks the Aberrantly Elevated Lipid Metabolism and Induces Apoptosis in Glioblastoma [RNA-Seq]

ABSTRACT: Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with poor survival rate and temozolomide (TMZ) has been used as the standard chemotherapy for GBM treatment. However, a large number of patients either respond poorly to TMZ and/or develop resistance after long-term use, urging the need for the development of potent drugs with novel mechanisms of action. Here, using high-throughput compound screening (HTS), we found azathioprine, an immunosuppressive medication, to be a promising therapeutic agent for TMZ-resistant GBM treatment. Through integrative genome-wide analysis and global proteomic analysis, we identified the elevated lipid metabolism due to hyperactive EGFR/AKT/SREBP-1 signaling pathway being inhibited by azathioprine. In addition, azathioprine causes ER stress-induced apoptosis. Orthotopic xenograft models injected with patient-derived GBM cells exhibits reduced tumor volumes and increased apoptosis by azathioprine. These overall data indicate that azathioprine could be a powerful therapeutic option for TMZ-resistant GBM patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153907 | GEO | 2021/02/16

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.

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Azathioprine Blocks the Aberrantly Elevated Lipid Metabolism and Induces Apoptosis in Glioblastoma [RNA-Seq]

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