Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression
Identifieur interne : 000A30 ( Main/Exploration ); précédent : 000A29; suivant : 000A31Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression
Auteurs : Alyssa La Belle Flynn [États-Unis] ; Benjamin C. Calhoun [États-Unis] ; Arishya Sharma [États-Unis] ; Jenny C. Chang [États-Unis] ; Alexandru Almasan [États-Unis] ; William P. Schiemann [États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2019.
Abstract
Breast cancer stem cells (BCSCs) are unique in their ability to undergo unlimited self-renewal, an essential process in breast cancer recurrence following metastatic dormancy. Emergent metastatic lesions were subjected to microarray analysis, which identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) as a differentially expressed gene coupled to metastatic recurrence. Here, we report that elevated Pfkfb3 expression correlates with the appearance of aggressive breast cancers and reduces relapse-free survival, as well as enhances BCSC self-renewal and metastatic outgrowth. We observe an inverse relationship between Pfkfb3 expression and autophagy, which reduces Pfkfb3 expression and elicits cellular dormancy. Targeted depletion of Atg3, Atg7, or p62/sequestosome-1 to inactivate autophagy restores aberrant Pfkfb3 expression in dormant BCSCs, leading to their reactivation of proliferative programs and outgrowth. Moreover, Pfkfb3 interacts physically with autophagy machinery, specifically the UBA domain of p62/sequestosome-1. Importantly, disrupting autophagy and this event enables Pfkfb3 to drive dormant BCSCs and metastatic lesions to recur.
Url:
DOI: 10.1038/s41467-019-11640-9
PubMed: 31413316
PubMed Central: 6694140
Affiliations:
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Schiemann</name><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2164 3847</institution-id><institution-id institution-id-type="GRID">grid.67105.35</institution-id><institution>Case Comprehensive Cancer Center,</institution><institution>Case Western Reserve University,</institution></institution-wrap>Cleveland, OH 44106 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Ohio</region></placeName><wicri:cityArea>Cleveland</wicri:cityArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</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">Breast cancer stem cells (BCSCs) are unique in their ability to undergo unlimited self-renewal, an essential process in breast cancer recurrence following metastatic dormancy. Emergent metastatic lesions were subjected to microarray analysis, which identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) as a differentially expressed gene coupled to metastatic recurrence. Here, we report that elevated Pfkfb3 expression correlates with the appearance of aggressive breast cancers and reduces relapse-free survival, as well as enhances BCSC self-renewal and metastatic outgrowth. We observe an inverse relationship between Pfkfb3 expression and autophagy, which reduces Pfkfb3 expression and elicits cellular dormancy. Targeted depletion of Atg3, Atg7, or p62/sequestosome-1 to inactivate autophagy restores aberrant Pfkfb3 expression in dormant BCSCs, leading to their reactivation of proliferative programs and outgrowth. Moreover, Pfkfb3 interacts physically with autophagy machinery, specifically the UBA domain of p62/sequestosome-1. 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Benjamin C" uniqKey="Calhoun B" first="Benjamin C." last="Calhoun">Benjamin C. Calhoun</name><name sortKey="Chang, Jenny C" sort="Chang, Jenny C" uniqKey="Chang J" first="Jenny C." last="Chang">Jenny C. Chang</name><name sortKey="Schiemann, William P" sort="Schiemann, William P" uniqKey="Schiemann W" first="William P." last="Schiemann">William P. Schiemann</name><name sortKey="Sharma, Arishya" sort="Sharma, Arishya" uniqKey="Sharma A" first="Arishya" last="Sharma">Arishya Sharma</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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