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ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells

Overview of attention for article published in Molecular Cancer, June 2017
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2 tweeters

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Title
ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells
Published in
Molecular Cancer, June 2017
DOI 10.1186/s12943-017-0667-y
Pubmed ID
Authors

Giulia Cesi, Geoffroy Walbrecq, Andreas Zimmer, Stephanie Kreis, Claude Haan

Abstract

Most melanoma patients with BRAF(V600E) positive tumors respond well to a combination of BRAF kinase and MEK inhibitors. However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment. For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets. Cellular metabolism is such a promising new target line: mutant BRAF(V600E) has been shown to affect the metabolism. Time course experiments and a series of western blots were performed in a panel of BRAF(V600E) and BRAF(WT)/NRAS(mut) human melanoma cells, which were incubated with BRAF and MEK1 kinase inhibitors. siRNA approaches were used to investigate the metabolic players involved. Reactive oxygen species (ROS) were measured by confocal microscopy and AZD7545, an inhibitor targeting PDKs (pyruvate dehydrogenase kinase) was tested. We show that inhibition of the RAS/RAF/MEK/ERK pathway induces phosphorylation of the pyruvate dehydrogenase PDH-E1α subunit in BRAF(V600E) and in BRAF(WT)/NRAS(mut) harboring cells. Inhibition of BRAF, MEK1 and siRNA knock-down of ERK1/2 mediated phosphorylation of PDH. siRNA-mediated knock-down of all PDKs or the use of DCA (a pan-PDK inhibitor) abolished PDH-E1α phosphorylation. BRAF inhibitor treatment also induced the upregulation of ROS, concomitantly with the induction of PDH phosphorylation. Suppression of ROS by MitoQ suppressed PDH-E1α phosphorylation, strongly suggesting that ROS mediate the activation of PDKs. Interestingly, the inhibition of PDK1 with AZD7545 specifically suppressed growth of BRAF-mutant and BRAF inhibitor resistant melanoma cells. In BRAF(V600E) and BRAF(WT)/NRAS(mut) melanoma cells, the increased production of ROS upon inhibition of the RAS/RAF/MEK/ERK pathway, is responsible for activating PDKs, which in turn phosphorylate and inactivate PDH. As part of a possible salvage pathway, the tricarboxylic acid cycle is inhibited leading to reduced oxidative metabolism and reduced ROS levels. We show that inhibition of PDKs by AZD7545 leads to growth suppression of BRAF-mutated and -inhibitor resistant melanoma cells. Thus small molecule PDK inhibitors such as AZD7545, might be promising drugs for combination treatment in melanoma patients with activating RAS/RAF/MEK/ERK pathway mutations (50% BRAF, 25% NRAS(mut), 11.9% NF1(mut)).

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 93 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 93 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 17 18%
Student > Master 14 15%
Researcher 12 13%
Student > Doctoral Student 9 10%
Student > Bachelor 8 9%
Other 10 11%
Unknown 23 25%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 30 32%
Agricultural and Biological Sciences 13 14%
Medicine and Dentistry 9 10%
Pharmacology, Toxicology and Pharmaceutical Science 3 3%
Neuroscience 2 2%
Other 12 13%
Unknown 24 26%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 November 2020.
All research outputs
#14,845,248
of 19,256,662 outputs
Outputs from Molecular Cancer
#957
of 1,459 outputs
Outputs of similar age
#195,178
of 282,552 outputs
Outputs of similar age from Molecular Cancer
#1
of 1 outputs
Altmetric has tracked 19,256,662 research outputs across all sources so far. This one is in the 19th percentile – i.e., 19% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,459 research outputs from this source. They receive a mean Attention Score of 4.3. This one is in the 27th percentile – i.e., 27% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 282,552 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 25th percentile – i.e., 25% of its contemporaries scored the same or lower than it.
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