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MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

Zirath, Hanna ; Frenzel, Anna ; Oliynyk, Ganna ; Segerstrom, Lova ; Westermark, Ulrica K. ; Larsson, Karin ; Thorén, Matilda LU ; Hultenby, Kjell ; Lehtio, Janne and Einvik, Christer , et al. (2013) In Proceedings of the National Academy of Sciences 110(25). p.10258-10263
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
mitochondria, fatty acid oxidation, oxidative phosphorylation, small, molecule, cancer therapy
in
Proceedings of the National Academy of Sciences
volume
110
issue
25
pages
10258 - 10263
publisher
National Academy of Sciences
external identifiers
  • wos:000321500200055
  • scopus:84879289434
ISSN
1091-6490
DOI
10.1073/pnas.1222404110
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)
id
9809ca01-8339-4c97-b3b7-eb4d7c5f41f2 (old id 4039656)
date added to LUP
2016-04-01 10:09:06
date last changed
2022-04-27 18:59:00
@article{9809ca01-8339-4c97-b3b7-eb4d7c5f41f2,
  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.}},
  author       = {{Zirath, Hanna and Frenzel, Anna and Oliynyk, Ganna and Segerstrom, Lova and Westermark, Ulrica K. and Larsson, Karin and Thorén, Matilda and Hultenby, Kjell and Lehtio, Janne and Einvik, Christer and Påhlman, Sven and Kogner, Per and Jakobsson, Per-Johan and Henriksson, Marie Arsenian}},
  issn         = {{1091-6490}},
  keywords     = {{mitochondria; fatty acid oxidation; oxidative phosphorylation; small; molecule; cancer therapy}},
  language     = {{eng}},
  number       = {{25}},
  pages        = {{10258--10263}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences}},
  title        = {{MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells}},
  url          = {{http://dx.doi.org/10.1073/pnas.1222404110}},
  doi          = {{10.1073/pnas.1222404110}},
  volume       = {{110}},
  year         = {{2013}},
}