About: Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells

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About: Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells
Creator	Reggiori, Fulvio Mari, Muriel Fulda, Simone Abou-El-Ardat, Khalil Kögel, Donat Meyer, Nina Zielke, Svenja Van Wijk, Sjoerd
Source	Medline; PMC
abstract	Autophagy is a well-described degradation mechanism that promotes cell survival upon nutrient starvation and other forms of cellular stresses. In addition, there is growing evidence showing that autophagy can exert a lethal function via autophagic cell death (ACD). As ACD has been implicated in apoptosis-resistant glioblastoma (GBM), there is a high medical need for identifying novel ACD-inducing drugs. Therefore, we screened a library containing 70 autophagy-inducing compounds to induce ATG5-dependent cell death in human MZ-54 GBM cells. Here, we identified three compounds, i.e. loperamide, pimozide, and STF-62247 that significantly induce cell death in several GBM cell lines compared to CRISPR/Cas9-generated ATG5- or ATG7-deficient cells, pointing to a death-promoting role of autophagy. Further cell death analyses conducted using pharmacological inhibitors revealed that apoptosis, ferroptosis, and necroptosis only play minor roles in loperamide-, pimozide- or STF-62247-induced cell death. Intriguingly, these three compounds induce massive lipidation of the autophagy marker protein LC3B as well as the formation of LC3B puncta, which are characteristic of autophagy. Furthermore, loperamide, pimozide, and STF-62247 enhance the autophagic flux in parental MZ-54 cells, but not in ATG5 or ATG7 knockout (KO) MZ-54 cells. In addition, loperamide- and pimozide-treated cells display a massive formation of autophagosomes and autolysosomes at the ultrastructural level. Finally, stimulation of autophagy by all three compounds is accompanied by dephosphorylation of mammalian target of rapamycin complex 1 (mTORC1), a well-known negative regulator of autophagy. In summary, our results indicate that loperamide, pimozide, and STF-62247 induce ATG5- and ATG7-dependent cell death in GBM cells, which is preceded by a massive induction of autophagy. These findings emphasize the lethal function and potential clinical relevance of hyperactivated autophagy in GBM.
has issue date	2018-09-24(xsd:dateTime)
bibo:doi	10.1038/s41419-018-1003-1
bibo:pmid	30250198
has license	cc-by
sha1sum (hex)	e5d1fd5c8ca1cb299a376d2b3109b4088b0c9ae5
schema:url	https://doi.org/10.1038/s41419-018-1003-1
resource representing a document's title	Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells
has PubMed Central identifier	PMC6155211
has PubMed identifier	30250198
schema:publication	Cell Death Dis
resource representing a document's body	covid:e5d1fd5c8ca1cb299a376d2b3109b4088b0c9ae5#body_text
is schema:about of	named entity 'induce' named entity 'parental' named entity 'knockout' named entity 'ATG7' named entity 'puncta' named entity 'necroptosis' named entity 'nutrient' named entity 'medical' named entity 'LOPERAMIDE' named entity 'PIMOZIDE' named entity 'LC3B' named entity 'MAMMALIAN TARGET OF RAPAMYCIN' named entity 'FUNCTION' named entity 'POINTING' named entity 'FLUX' named entity 'LEVEL' named entity 'THESE' named entity 'CHARACTERISTIC' named entity 'ATG7' named entity 'GBM' named entity 'IDENTIFIED' named entity 'STF-62247' named entity 'REVEALED' covid:arg/e5d1fd5c8ca1cb299a376d2b3109b4088b0c9ae5 named entity 'TARGET OF RAPAMYCIN COMPLEX 1' named entity 'LETHAL' named entity 'DISPLAY' named entity 'NUTRIENT STARVATION' named entity 'AUTOPHAGIC CELL DEATH' named entity 'CLINICAL RELEVANCE' named entity 'PLAY' named entity 'OUR' named entity 'PIMOZIDE' named entity 'LOPERAMIDE' named entity 'DEPHOSPHORYLATION' named entity 'GROWING' named entity 'DEPENDENT' named entity 'KNOWN' named entity 'NOVEL' named entity 'CRISPR' named entity 'GENERATED' named entity 'PARENTAL' named entity 'GLIOBLASTOMA CELLS' named entity 'CELL DEATH' named entity 'TRIGGER' named entity 'AUTOPHAGY' named entity 'IS A' named entity 'NEED FOR' named entity 'BUT' named entity 'SUMMARY' named entity 'CONTAINING' named entity 'DEATH' named entity 'AUTOPHAGOSOMES' named entity 'DESCRIBED' named entity 'HUMAN' named entity 'CELL DEATH' named entity 'HERE' named entity 'CELL SURVIVAL' named entity 'APOPTOSIS' named entity 'ROLE' named entity 'MEDICAL' named entity 'GBM CELL' named entity 'MECHANISM' named entity 'GLIOBLASTOMA' named entity 'NEGATIVE REGULATOR' named entity 'ADDITION' named entity 'USING' named entity 'DEGRADATION' named entity 'FERROPTOSIS' named entity 'STRESSES' named entity 'ROLES' named entity 'KNOCKOUT' named entity 'POTENTIAL' named entity 'ACD'

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