PXD033503

PXD033503 is an original dataset announced via ProteomeXchange.

Title	Inhibition of mTOR signaling protects human glioma-cells from starvation-induced cell death in an autophagy-independent manner
Description	Although malignant gliomas frequently show aberrant activation of the mammalian target of rapamycin (mTOR), mTOR inhibitors have performed poorly in clinical trials. Besides regulating cell growth and translation, mTOR controls the initiation of autophagy. By recycling cellular components, autophagy can mobilize energy resources, and has thus been attributed cancer-promoting effects. Here, we asked whether the activation of autophagy represents an escape mechanism to pharmacological mTOR inhibition, and explored co-treatment with mTOR and autophagy inhibitors as a therapeutic strategy. Mimicking conditions of the glioma microenvironment, glioma cells were exposed to nutrient starvation and hypoxia. Following treatment with mTOR inhibitor torin2 or rapamycin, and autophagy inhibitors bafilomycin A1 or MRT68921, we analyzed autophagic activity, cell growth, viability and oxygen consumption. Changes in global proteome were quantified by mass spectrometry. In the context of hypoxia and starvation, autophagy was strongly induced in glioma cells, and further increased by mTOR inhibition. While torin2 enhanced glioma cell survival, co-treatment with torin2 and bafilomycin A1 failed to promote cell death. Importantly, treatment with bafilomycin A1 alone also protected glioma cells from cell death. Mechanistically, both compounds significantly reduced glioma growth and oxygen consumption. Mass spectrometry analysis showed that bafilomycin A1 induced broad changes in the cellular proteome. More specifically, proteins downregulated by bafilomycin A1 were associated with the mitochondrial respiratory chain and ATP synthesis. Taken together, our results show that activation of autophagy does not account for the cytoprotective effects of mTOR inhibition in our in vitro model of the glioma microenvironment. Our proteomic findings suggest that the pharmacological inhibition of autophagy induces extensive changes in the cellular proteome that can support glioma cell survival under nutrient-deplete and hypoxic conditions. These findings provide a novel perspective on the complex role of autophagy in gliomas and may have implications for the design of future trials.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_06:49:27.044.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Iris Divé
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-28 01:01:43	ID requested
1	2022-10-13 13:14:58	announced
⏵ 2	2023-11-14 06:49:27	announced	2023-11-14: Updated project metadata.

Div, é I, Klann K, Michaelis JB, Heinzen D, Steinbach JP, M, ü, nch C, Ronellenfitsch MW, Inhibition of mTOR signaling protects human glioma cells from hypoxia-induced cell death in an autophagy-independent manner. Cell Death Discov, 8(1):409(2022) [pubmed]

submitter keyword: Human, Autophagy, Glioma, mTOR

Christian Münch
contact affiliation	Institute of Biochemistry II, Goethe University Frankfurt, Germany
contact email	ch.muench@em.uni-frankfurt.de
lab head
Iris Divé
contact affiliation	Goethe University Frankfurt
contact email	iris.dive@kgu.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD033503
     1. Label: PRIDE project
     2. Name: Inhibition of mTOR signaling protects human glioma-cells from starvation-induced cell death in an autophagy-independent manner