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dc.contributor.authorSundstrøm, Terje
dc.contributor.authorPrestegarden, Lars
dc.contributor.authorAzuaje, Francisco
dc.contributor.authorAasen, Synnøve Nymark
dc.contributor.authorRøsland, Gro Vatne
dc.contributor.authorVarughese, Jobin K.
dc.contributor.authorBahador, Marzieh
dc.contributor.authorBernatz, Simon
dc.contributor.authorBraun, Yannick
dc.contributor.authorHarter, Patrick N.
dc.contributor.authorSkaftnesmo, Kai Ove
dc.contributor.authorIngham, Elizabeth S.
dc.contributor.authorMahakian, Lisa M.
dc.contributor.authorTam, Sarah
dc.contributor.authorTepper, Clifford G.
dc.contributor.authorPetersen, Kjell
dc.contributor.authorFerrara, Katherine W.
dc.contributor.authorTronstad, Karl Johan
dc.contributor.authorLund-Johansen, Morten
dc.contributor.authorBeschorner, Rudi
dc.contributor.authorBjerkvig, Rolf
dc.contributor.authorThorsen, Frits
dc.date.accessioned2019-08-29T11:56:07Z
dc.date.available2019-08-29T11:56:07Z
dc.date.created2019-07-04T12:31:02Z
dc.date.issued2019
dc.identifier.citationActa neuropathologica communications. 2019, 7:55 1-19.nb_NO
dc.identifier.issn2051-5960
dc.identifier.urihttp://hdl.handle.net/11250/2611636
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.nb_NO
dc.language.isoengnb_NO
dc.titleInhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasisnb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.description.versionpublishedVersionnb_NO
dc.source.pagenumber1-19nb_NO
dc.source.volume7:55nb_NO
dc.source.journalActa neuropathologica communicationsnb_NO
dc.identifier.doi10.1186/s40478-019-0712-8
dc.identifier.cristin1710086
dc.relation.projectNorges forskningsråd: 214187nb_NO
dc.relation.projectHelse Vest RHF: 911990nb_NO
dc.relation.projectHelse Vest RHF: 911645nb_NO
dc.relation.projectNorges forskningsråd: 214381nb_NO
dc.relation.projectUniversitetet i Bergen: 710028nb_NO
dc.relation.projectHelse Vest RHF: 911558nb_NO
dc.relation.projectUniversitetet i Bergen: 236608nb_NO
cristin.unitcode7431,24,0,0
cristin.unitnameReproduksjon og utvikl.biologi
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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