Abstract
Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. RSK directly phosphorylated the regulatory domain of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), an enzyme that catalyzes the synthesis of fructose-2,6-bisphosphate during glycolysis. Inhibition of RSK reduced PFKFB2 activity and glycolytic flux in melanoma cells, suggesting an important role for RSK in BRAF-mediated metabolic rewiring. Consistent with this, expression of a phosphorylation-deficient mutant of PFKFB2 decreased aerobic glycolysis and reduced the growth of melanoma in mice. Together, these results indicate that RSK-mediated phosphorylation of PFKFB2 plays a key role in the metabolism and growth of BRAF-mutated melanomas.Significance: RSK promotes glycolytic metabolism and the growth of BRAF-mutated melanoma by driving phosphorylation of an important glycolytic enzyme. Cancer Res; 78(9); 2191-204. ©2018 AACR.
Highlights
Melanoma is the most aggressive form of skin cancer and arises from melanocytes, which reside in the skin, eye, mucosal epithelia, and meninges of the brain and spinal cord [1]
In order to dissect its contributions on the regulation of glycolysis, we examined the effects of specific enzyme inhibitors on the metabolism in BRAF-mutated melanoma cell
We show that the MAPK-activated protein kinase ribosomal S6 kinase (RSK) regulates glucose metabolism in melanoma cell lines with a BRAF V600E mutation (Fig. 1)
Summary
Melanoma is the most aggressive form of skin cancer and arises from melanocytes, which reside in the skin, eye, mucosal epithelia, and meninges of the brain and spinal cord [1]. The RAS/MAPK pathway is frequently activated due to mutations in BRAF (52%), NRAS (28%), and NF1 (14%) genes [2]. More than 90% of BRAF mutations encode a protein harboring the V600E mutation, which constitutively activates ERK 1/2 signaling and drives cell proliferation [3,4,5]. Malignant melanoma is highly resistant to conventional chemotherapy [6], Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Gravel: Faculty of Pharmacy, Universite de Montreal, Montreal, Quebec, Canada; current address for M. Savall: Institut Cochin, Universite Paris Descartes (Paris V); Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France; Institut National de la sante et de la recherche medicale (INSERM), U1016, Paris 75014, France; and current address for J.
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