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Gubat, Johannes,1986-Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
(författare)
Comprehensive Target Screening and Cellular Profiling of the Cancer-Active Compound b-AP15 Indicate Abrogation of Protein Homeostasis and Organelle Dysfunction as the Primary Mechanism of Action
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
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2022-04-22
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Frontiers Media SA,2022
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:liu-184797
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-184797URI
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https://doi.org/10.3389/fonc.2022.852980DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:151013531URI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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Funding: This research was funded by Cancerfonden, Vetenskapsrådet (grant 2018-02570) and Radiumhemmets forskningsfonder. CFG acknowledges support from the National Genomics Infrastructure, SNIC (project 2017-7-265), and the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX). RZ acknowledges the Knut and Alice Wallenberg Foundation (grant KAW 2015.0063).
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Dienone compounds have been demonstrated to display tumor-selective anti-cancer activity independently of the mutational status of TP53. Previous studies have shown that cell death elicited by this class of compounds is associated with inhibition of the ubiquitin-proteasome system (UPS). Here we extend previous findings by showing that the dienone compound b-AP15 inhibits proteasomal degradation of long-lived proteins. We show that exposure to b-AP15 results in increased association of the chaperones VCP/p97/Cdc48 and BAG6 with proteasomes. Comparisons between the gene expression profile generated by b-AP15 to those elicited by siRNA showed that knock-down of the proteasome-associated deubiquitinase (DUB) USP14 is the closest related to drug response. USP14 is a validated target for b-AP15 and we show that b-AP15 binds covalently to two cysteines, Cys203 and Cys257, in the ubiquitin-binding pocket of the enzyme. Consistent with this, deletion of USP14 resulted in decreased sensitivity to b-AP15. Targeting of USP14 was, however, found to not fully account for the observed proteasome inhibition. In search for additional targets, we utilized genome-wide CRISPR/Cas9 library screening and Proteome Integral Solubility Alteration (PISA) to identify mechanistically essential genes and b-AP15 interacting proteins respectively. Deletion of genes encoding mitochondrial proteins decreased the sensitivity to b-AP15, suggesting that mitochondrial dysfunction is coupled to cell death induced by b-AP15. Enzymes known to be involved in Phase II detoxification such as aldo-ketoreductases and glutathione-S-transferases were identified as b-AP15-targets using PISA. The finding that different exploratory approaches yielded different results may be explained in terms of a “target” not necessarily connected to the “mechanism of action” thus highlighting the importance of a holistic approach in the identification of drug targets. We conclude that b-AP15, and likely also other dienone compounds of the same class, affect protein degradation and proteasome function at more than one level.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Selvaraju, Karthik,1983-Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten(Swepub:liu)karse35
(författare)
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Sjöstrand, LindaLinköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten(Swepub:liu)linsj98
(författare)
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Kumar Singh, DhananjayLinköpings universitet,Institutionen för biomedicinska och kliniska vetenskaper,Medicinska fakulteten,Department of Pharmacy, Central University of South Bihar, Gaya, India(Swepub:liu)dhasi22
(författare)
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Turkina, Maria V,1973-Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten(Swepub:liu)martu07
(författare)
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Schmierer, BernhardKarolinska Institutet,Department of Medical Biochemistry and Biophysics, Division of Chemical Biology, Karolinska Institutet, Stockholm, Sweden
(författare)
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Sabatier, PierreDepartment of Medical Biochemistry and Biophysics, Division of Physiological Chemistry I, Karolinska Institutet, Stockholm, Sweden
(författare)
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Zubarev, Roman A.Karolinska Institutet,Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry I, Karolinska Institutet, Stockholm, Sweden; Department of Pharmacological and Technological Chemistry, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
(författare)
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Linder, Stig,1954-Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden(Swepub:liu)stili13
(författare)
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D´arcy, Pádraig,1978-Karolinska Institutet,Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten(Swepub:liu)padda29
(författare)
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Linköpings universitetAvdelningen för klinisk kemi och farmakologi
(creator_code:org_t)
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Ingår i:Frontiers in Oncology: Frontiers Media SA122234-943X
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Gubat, Johannes, ...
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Turkina, Maria V ...
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Schmierer, Bernh ...
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Sabatier, Pierre
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