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dc.contributor.authorSundstrøm, Terjeen_US
dc.contributor.authorPrestegarden, Larsen_US
dc.contributor.authorAzuaje, Franciscoen_US
dc.contributor.authorAasen, Synnøve Nymarken_US
dc.contributor.authorRøsland, Gro Vatneen_US
dc.contributor.authorVarughese, Jobin K.en_US
dc.contributor.authorBahador, Marziehen_US
dc.contributor.authorBernatz, Simonen_US
dc.contributor.authorBraun, Yannicken_US
dc.contributor.authorHarter, Patrick N.en_US
dc.contributor.authorSkaftnesmo, Kai Oveen_US
dc.contributor.authorIngham, Elizabeth S.en_US
dc.contributor.authorMahakian, Lisa M.en_US
dc.contributor.authorTam, Sarahen_US
dc.contributor.authorTepper, Clifford G.en_US
dc.contributor.authorPetersen, Kjellen_US
dc.contributor.authorFerrara, Katherine W.en_US
dc.contributor.authorTronstad, Karl Johanen_US
dc.contributor.authorLund-Johansen, Mortenen_US
dc.contributor.authorBeschorner, Rudien_US
dc.contributor.authorBjerkvig, Rolfen_US
dc.contributor.authorThorsen, Fritsen_US
dc.PublishedSundstrøm T, Prestegarden L, Azuaje F, Aasen SN, Røsland GV, Varughese JK, Bahador M, Bernatz, Braun, Harter PN, Skaftnesmo KO, Ingham, Mahakian LM, Tam, Tepper, Petersen K, Ferrara KW, Tronstad KJ, Lund-Johansen M, Beschorner R, Bjerkvig R, Thorsen F. Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis. Acta neuropathologica communications. 2019;7:55eng
dc.description.abstractMelanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. Augmented mitochondrial respiration is a key resistance mechanism in BRAF-mutant melanomas but, as we show in this study, this dependence on mitochondrial respiration may also be exploited therapeutically. We first used high-throughput pharmacogenomic profiling to identify potentially repurposable compounds against BRAF-mutant melanoma brain metastases. One of the compounds identified was β-sitosterol, a well-tolerated and brain-penetrable phytosterol. Here we show that β-sitosterol attenuates melanoma cell growth in vitro and also inhibits brain metastasis formation in vivo. Functional analyses indicated that the therapeutic potential of β-sitosterol was linked to mitochondrial interference. Mechanistically, β-sitosterol effectively reduced mitochondrial respiratory capacity, mediated by an inhibition of mitochondrial complex I. The net result of this action was increased oxidative stress that led to apoptosis. This effect was only seen in tumor cells, and not in normal cells. Large-scale analyses of human melanoma brain metastases indicated a significant role of mitochondrial complex I compared to brain metastases from other cancers. Finally, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. In conclusion, based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases.en_US
dc.publisherBioMed Centraleng
dc.rightsAttribution CC BYeng
dc.subjectBrain metastasiseng
dc.subjectBRAF V600Eeng
dc.titleInhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasisen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2019 The Author(s)
dc.source.journalActa neuropathologica communications
dc.relation.projectUniversitetet i Bergen: 710028
dc.relation.projectNorges forskningsråd: 214187
dc.relation.projectHelse Vest RHF: 911990
dc.relation.projectUniversitetet i Bergen: 236608
dc.relation.projectHelse Vest RHF: 911558
dc.relation.projectHelse Vest RHF: 911645
dc.relation.projectNorges forskningsråd: 214381

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