دورية أكاديمية
أعرض في EDS

Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma.

التفاصيل البيبلوغرافية
العنوان: Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma.
المؤلفون: Huang F; Lady Davis Institute.; Department of Experimental Medicine, and., Cai F; Lady Davis Institute.; Department of Experimental Medicine, and., Dahabieh MS; Lady Davis Institute.; Department of Experimental Medicine, and., Gunawardena K; Lady Davis Institute., Talebi A; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Dehairs J; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., El-Turk F; McGill University Health Centre, Montreal, Quebec, Canada.; Centre Hospitalier Universitaire Sainte Justine, Montreal, Quebec, Canada., Park JY; McGill University Health Centre, Montreal, Quebec, Canada., Li M; Lady Davis Institute.; Department of Experimental Medicine, and., Goncalves C; Lady Davis Institute., Gagnon N; Lady Davis Institute., Su J; Lady Davis Institute., LaPierre JH; Lady Davis Institute.; Department of Experimental Medicine, and., Gaub P; Centre de Recherche, CHU St. Justine, Montréal, Quebec, Canada., Joyal JS; Centre de Recherche, CHU St. Justine, Montréal, Quebec, Canada., Mitchell JJ; McGill University Health Centre, Montreal, Quebec, Canada., Swinnen JV; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Miller WH Jr; Lady Davis Institute.; Department of Experimental Medicine, and.; Department of Oncology, McGill University, Montreal, Quebec, Canada., Del Rincón SV; Lady Davis Institute.; Department of Experimental Medicine, and.; Department of Oncology, McGill University, Montreal, Quebec, Canada.
المصدر: The Journal of clinical investigation [J Clin Invest] 2023 Oct 16; Vol. 133 (20). Date of Electronic Publication: 2023 Oct 16.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Peroxisomes*/metabolism , Melanoma*/genetics, Humans ; Lipid Metabolism ; Ceramides/pharmacology ; Ceramides/metabolism
مستخلص: Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.
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معلومات مُعتمدة: PJT-162260 Canada CIHR
فهرسة مساهمة: Keywords: Melanoma; Oncology
المشرفين على المادة: 0 (Ceramides)
تواريخ الأحداث: Date Created: 20230824 Date Completed: 20231023 Latest Revision: 20231024
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10575734
DOI: 10.1172/JCI166644
PMID: 37616051
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI166644