Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt‐based anti‐cancer drugs

  1. Planells‐Cases, Rosa
  2. Lutter, Darius
  3. Guyader, Charlotte
  4. Gerhards, Nora M.
  5. Ullrich, Florian ORCID logo
  6. Elger, Deborah A.
  7. Kucukosmanoglu, Asli
  8. Xu, Guotai
  9. Voss, Felizia K.
  10. Reincke, Momsen ORCID logo
  11. Stauber, Tobias ORCID logo
  12. Blomen, Vincent A.
  13. Vis, Daniel J.
  14. Wessels, Lodewyk F.
  15. Brummelkamp, Thijn R.
  16. Borst, Piet
  17. Rottenberg, Sven
  18. Jentsch, Thomas ORCID logo

Download
EMBJ-34-2993.pdf 2,12MB
WeightNameValue
1000 Titel
  • Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt‐based anti‐cancer drugs
1000 Autor/in
  1. Planells‐Cases, Rosa |
  2. Lutter, Darius |
  3. Guyader, Charlotte |
  4. Gerhards, Nora M. |
  5. Ullrich, Florian |
  6. Elger, Deborah A. |
  7. Kucukosmanoglu, Asli |
  8. Xu, Guotai |
  9. Voss, Felizia K. |
  10. Reincke, Momsen |
  11. Stauber, Tobias |
  12. Blomen, Vincent A. |
  13. Vis, Daniel J. |
  14. Wessels, Lodewyk F. |
  15. Brummelkamp, Thijn R. |
  16. Borst, Piet |
  17. Rottenberg, Sven |
  18. Jentsch, Thomas |
1000 Erscheinungsjahr 2015
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2015-11-03
1000 Erschienen in
1000 Quellenangabe
  • 34(24): 2985-3073
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2015
1000 Lizenz
1000 Verlagsversion
  • https://dx.doi.org/10.15252/embj.201592409 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687416/ |
1000 Ergänzendes Material
  • http://emboj.embopress.org/content/34/24/2993.figures-only#fig-data-supplementary-materials |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Although platinum‐based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume‐regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8‐dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug‐induced apoptosis independently from drug uptake, possibly by impairing VRAC‐dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D‐containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.
1000 Sacherschließung
lokal VSOR
lokal chloride channel
lokal swelling‐activated
lokal haploid cell screen
lokal VSOAC
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/UGxhbmVsbHPigJBDYXNlcyzCoFJvc2E=|https://frl.publisso.de/adhoc/creator/THV0dGVyLMKgRGFyaXVz|https://frl.publisso.de/adhoc/creator/R3V5YWRlcizCoENoYXJsb3R0ZQ==|https://frl.publisso.de/adhoc/creator/R2VyaGFyZHMsIE5vcmEgTS4=|http://orcid.org/0000-0002-1153-2040|https://frl.publisso.de/adhoc/creator/RWxnZXIswqBEZWJvcmFoIEEu|https://frl.publisso.de/adhoc/creator/S3VjdWtvc21hbm9nbHUsIEFzbGk=|https://frl.publisso.de/adhoc/creator/WHUswqBHdW90YWk=|https://frl.publisso.de/adhoc/creator/Vm9zcyzCoEZlbGl6aWEgSy4=|http://orcid.org/0000-0002-8132-3527|http://orcid.org/0000-0003-0727-6109|https://frl.publisso.de/adhoc/creator/QmxvbWVuLMKgVmluY2VudCBBLg==|https://frl.publisso.de/adhoc/creator/VmlzLMKgRGFuaWVsIEou|https://frl.publisso.de/adhoc/creator/V2Vzc2VscyzCoExvZGV3eWsgRi4=|https://frl.publisso.de/adhoc/creator/QnJ1bW1lbGthbXAswqBUaGlqbiBSLg==|https://frl.publisso.de/adhoc/creator/Qm9yc3QswqBQaWV0|https://frl.publisso.de/adhoc/creator/Um90dGVuYmVyZyzCoFN2ZW4=|http://orcid.org/0000-0002-3509-2553
1000 Label
1000 Förderer
  1. European Research Council |
  2. European Union |
  3. Deutsche Forschungsgemeinschaft (DFG) |
  4. Netherlands Organization for Scientific Research |
  5. Swiss National Science Foundation |
1000 Fördernummer
  1. 294435
  2. -
  3. -
  4. NWO‐VIDI 016.116.302
  5. P1BEP3_155461
1000 Förderprogramm
  1. Advanced Grant: “Cytovolion”
  2. FP/2007‐2013
  3. Exc 257 “NeuroCure”
  4. -
  5. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer European Research Council |
    1000 Förderprogramm Advanced Grant: “Cytovolion”
    1000 Fördernummer 294435
  2. 1000 joinedFunding-child
    1000 Förderer European Union |
    1000 Förderprogramm FP/2007‐2013
    1000 Fördernummer -
  3. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft (DFG) |
    1000 Förderprogramm Exc 257 “NeuroCure”
    1000 Fördernummer -
  4. 1000 joinedFunding-child
    1000 Förderer Netherlands Organization for Scientific Research |
    1000 Förderprogramm -
    1000 Fördernummer NWO‐VIDI 016.116.302
  5. 1000 joinedFunding-child
    1000 Förderer Swiss National Science Foundation |
    1000 Förderprogramm -
    1000 Fördernummer P1BEP3_155461
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6404689.rdf
1000 Erstellt am 2017-09-26T11:56:11.917+0200
1000 Erstellt von 218
1000 beschreibt frl:6404689
1000 Bearbeitet von 218
1000 Zuletzt bearbeitet Thu Aug 18 07:52:24 CEST 2022
1000 Objekt bearb. Thu Aug 26 10:44:43 CEST 2021
1000 Vgl. frl:6404689
1000 Oai Id
  1. oai:frl.publisso.de:frl:6404689 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

View source