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Ultrafast proteomics revealed everolimus-induced inhibition of 20S proteasome subunit

ABSTRACT: In this study, we compare the proteomic responses of three cell lines (A549, HCT116, and MCF-7) to treatment with three antitumor drugs (bortezomib, everolimus, and lonidamine), with a particular focus on the effects on the ubiquitin-proteasome system. Liquid chromatography–mass spectrometry (LC-MS) experiments for cellular samples were conducted using an Orbitrap Q Exactive HF mass spectrometer, and the data were analyzed utilizing the DirectMS1 method. Cellular samples treated with bortezomib and lonidamine served as negative and positive controls, respectively, while the samples treated with everolimus constituted the primary subject of investigation.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Colon Cancer,Breast Cancer

SUBMITTER: Elizaveta Kazakova

LAB HEAD: Mikhail V. Gorshkov

PROVIDER: PXD060076 | Pride | 2026-07-20

REPOSITORIES: Pride

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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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Ultrafast proteomics revealed everolimus-induced inhibition of 20S proteasome subunit

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