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: Hanna Zirath, Anna Frenzel, Ganna Oliynyk, Lova Segerström, Ulrica K Westermark, Karin Larsson, Matilda Munksgaard Persson, Kjell Hultenby, Janne Lehtiö, Christer Einvik, Sven Påhlman, Per Kogner, Per-Johan Jakobsson, Marie Arsenian Henriksson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 25 Pg. 10258-63 (Jun 18 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23733953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one
• Antineoplastic Agents
• Fatty Acids
• Proto-Oncogene Proteins c-myc
• Thiazoles
• Receptor, trkA

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Electron Transport (drug effects)
• Fatty Acids (metabolism)
• Humans
• Lipid Metabolism (drug effects)
• Mice
• Mice, Nude
• Mice, Transgenic
• Mitochondria (drug effects, metabolism)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors, metabolism)
• Receptor, trkA (metabolism)
• Signal Transduction (drug effects)
• Thiazoles (pharmacology)
• Xenograft Model Antitumor Assays