Effect of early-stage autophagy inhibition in BRAFV600E autophagy-dependent brain tumor cells
Identifieur interne : 000A23 ( Ncbi/Curation ); précédent : 000A22; suivant : 000A24Effect of early-stage autophagy inhibition in BRAFV600E autophagy-dependent brain tumor cells
Auteurs : Shadi Zahedi [États-Unis] ; Brent E. Fitzwalter [États-Unis] ; Andrew Morin [États-Unis] ; Sydney Grob [États-Unis] ; Michele Desmarais [États-Unis] ; Anandani Nellan [États-Unis] ; Adam L. Green [États-Unis] ; Rajeev Vibhakar [États-Unis] ; Todd C. Hankinson [États-Unis] ; Nicholas K. Foreman [États-Unis] ; Jean M. Mulcahy Levy [États-Unis]Source :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
Autophagy is a multistage process. Progress within the field has led to the development of agents targeting both early (initiation) and late (fusion) stages of this process. The specific stage of autophagy targeted may influence cancer treatment outcomes. We have previously shown that central nervous system (CNS) tumors with the
Url:
DOI: 10.1038/s41419-019-1880-y
PubMed: 31515514
PubMed Central: 6742667
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PMC:6742667Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Effect of early-stage autophagy inhibition in BRAF<sup>V600E</sup>
autophagy-dependent brain tumor cells</title>
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<institution>University of Colorado Denver,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0690 7621</institution-id>
<institution-id institution-id-type="GRID">grid.413957.d</institution-id>
<institution>The Morgan Adams Foundation Pediatric Brain Tumor Research Program,</institution>
<institution>Children’s Hospital Colorado,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Green, Adam L" sort="Green, Adam L" uniqKey="Green A" first="Adam L." last="Green">Adam L. Green</name>
<affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0703 675X</institution-id>
<institution-id institution-id-type="GRID">grid.430503.1</institution-id>
<institution>Department of Pediatrics,</institution>
<institution>University of Colorado Denver,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0690 7621</institution-id>
<institution-id institution-id-type="GRID">grid.413957.d</institution-id>
<institution>The Morgan Adams Foundation Pediatric Brain Tumor Research Program,</institution>
<institution>Children’s Hospital Colorado,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Vibhakar, Rajeev" sort="Vibhakar, Rajeev" uniqKey="Vibhakar R" first="Rajeev" last="Vibhakar">Rajeev Vibhakar</name>
<affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0703 675X</institution-id>
<institution-id institution-id-type="GRID">grid.430503.1</institution-id>
<institution>Department of Pediatrics,</institution>
<institution>University of Colorado Denver,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0690 7621</institution-id>
<institution-id institution-id-type="GRID">grid.413957.d</institution-id>
<institution>The Morgan Adams Foundation Pediatric Brain Tumor Research Program,</institution>
<institution>Children’s Hospital Colorado,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Hankinson, Todd C" sort="Hankinson, Todd C" uniqKey="Hankinson T" first="Todd C." last="Hankinson">Todd C. Hankinson</name>
<affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0690 7621</institution-id>
<institution-id institution-id-type="GRID">grid.413957.d</institution-id>
<institution>The Morgan Adams Foundation Pediatric Brain Tumor Research Program,</institution>
<institution>Children’s Hospital Colorado,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0703 675X</institution-id>
<institution-id institution-id-type="GRID">grid.430503.1</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>University of Colorado Denver,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Foreman, Nicholas K" sort="Foreman, Nicholas K" uniqKey="Foreman N" first="Nicholas K." last="Foreman">Nicholas K. Foreman</name>
<affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0703 675X</institution-id>
<institution-id institution-id-type="GRID">grid.430503.1</institution-id>
<institution>Department of Pediatrics,</institution>
<institution>University of Colorado Denver,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0690 7621</institution-id>
<institution-id institution-id-type="GRID">grid.413957.d</institution-id>
<institution>The Morgan Adams Foundation Pediatric Brain Tumor Research Program,</institution>
<institution>Children’s Hospital Colorado,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mulcahy Levy, Jean M" sort="Mulcahy Levy, Jean M" uniqKey="Mulcahy Levy J" first="Jean M." last="Mulcahy Levy">Jean M. Mulcahy Levy</name>
<affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0703 675X</institution-id>
<institution-id institution-id-type="GRID">grid.430503.1</institution-id>
<institution>Department of Pediatrics,</institution>
<institution>University of Colorado Denver,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0690 7621</institution-id>
<institution-id institution-id-type="GRID">grid.413957.d</institution-id>
<institution>The Morgan Adams Foundation Pediatric Brain Tumor Research Program,</institution>
<institution>Children’s Hospital Colorado,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0703 675X</institution-id>
<institution-id institution-id-type="GRID">grid.430503.1</institution-id>
<institution>Department of Pharmacology,</institution>
<institution>University of Colorado Denver,</institution>
</institution-wrap>
Aurora, CO USA</nlm:aff>
<country>États-Unis</country>
<placeName><region type="state">Colorado</region>
</placeName>
<wicri:cityArea>Aurora</wicri:cityArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Death & Disease</title>
<idno type="eISSN">2041-4889</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="Par1">Autophagy is a multistage process. Progress within the field has led to the development of agents targeting both early (initiation) and late (fusion) stages of this process. The specific stage of autophagy targeted may influence cancer treatment outcomes. We have previously shown that central nervous system (CNS) tumors with the <italic>BRAF</italic>
<sup><italic>V600E</italic>
</sup>
mutation are autophagy dependent, and late-stage autophagy inhibition improves the response to targeted BRAF inhibitors (BRAFi) in sensitive and resistant cells. Drugs directed toward initiation of autophagy have been shown to reduce tumor cell death in some cancers, but have not been assessed in CNS tumors. We investigated early-stage inhibition for autophagy-dependent CNS tumors. BRAFi-sensitive and resistant AM38 and MAF794 cell lines were evaluated for the response to pharmacologic and genetic inhibition of ULK1 and VPS34, two crucial subunits of the autophagy initiation complexes. Changes in autophagy were monitored by western blot and flow cytometry. Survival was evaluated in short- and long-term growth assays. Tumor cells exhibited a reduced autophagic flux with pharmacologic and genetic inhibition of ULK1 or VPS34. Pharmacologic inhibition reduced cell survival in a dose-dependent manner for both targets. Genetic inhibition reduced cell survival and confirmed that it was an autophagy-specific effect. Pharmacologic and genetic inhibition were also synergistic with BRAFi, irrespective of RAFi sensitivity. Inhibition of ULK1 and VPS34 are potentially viable clinical targets in autophagy-dependent CNS tumors. Further evaluation is needed to determine if early-stage autophagy inhibition is equal to late-stage inhibition to determine the optimal clinical target for patients.</p>
</div>
</front>
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</listBibl>
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</TEI>
</record>
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