PXD021828

PXD021828 is an original dataset announced via ProteomeXchange.

Title	Bortezomib abrogates temozolomide-induced autophagic flux and kills glioblastoma cells through an ATG5 and ATG7 dependent pathway
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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:18:35.095.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Even Birkeland
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive; LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-05 03:51:36	ID requested
1	2023-03-10 15:31:20	announced
⏵ 2	2023-11-14 08:18:36	announced	2023-11-14: Updated project metadata.

Rahman MA, Engelsen AST, Sarowar S, Bindesb, ø, ll C, Birkeland E, Goplen D, Lotsberg ML, Knappskog S, Simonsen A, Chekenya M, Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway. Front Cell Dev Biol, 10():1022191(2022) [pubmed]

submitter keyword: Bortezomib abrogates temozolomide-induced autophagic flux and kills glioblastoma cells through an ATG5 and ATG7 dependent pathway

Martha Chekenya
contact affiliation	University of Bergen, Department of Clinical Science, Norway
contact email	martha.enger@uib.no
lab head
Even Birkeland
contact affiliation	Institute of biomedicine, University of BErgen
contact email	even.birkeland@uib.no
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021828
     1. Label: PRIDE project
     2. Name: Bortezomib abrogates temozolomide-induced autophagic flux and kills glioblastoma cells through an ATG5 and ATG7 dependent pathway