title: MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells.
abstract: The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Zirath
authors.forename: Anna
authors.initials: A
authors.lastname: Frenzel
authors.forename: Ganna
authors.initials: G
authors.lastname: Oliynyk
authors.forename: Lova
authors.initials: L
authors.lastname: Segerström
authors.forename: Ulrica K
authors.initials: UK
authors.lastname: Westermark
authors.forename: Karin
authors.initials: K
authors.lastname: Larsson
authors.forename: Matilda
authors.initials: M
authors.lastname: Munksgaard Persson
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.forename: Christer
authors.initials: C
authors.lastname: Einvik
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Marie Arsenian
authors.initials: MA
authors.lastname: Henriksson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004579:Electron Transport / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D000970:Antineoplastic Agents; D005227:Fatty Acids; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; D020917:Receptor, trkA
keywords: cancer therapy; fatty acid oxidation; mitochondria; oxidative phosphorylation; small molecule