Abstract
Dysregulation of metabolism during melanoma progression is tightly associated with the acquisition of genetic and epigenetic alterations in regulators of metabolic pathways. Retinoic acid receptor beta (RARβ) is epigenetically silenced in a large proportion of melanomas, but a link between RARβ and metabolic rewiring of melanoma has not been established. Here, we show that in primary human melanocytes, all-trans retinoic acid (a RARβ agonist) induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RARβ led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis. In melanoma cells, inhibition of RARβ promoted lower mitochondrial respiration and higher glycolytic activity, which led to energetic stress and activation of the energy sensor AMP-activated protein kinase. This metabolic shift increased the sensitivity to both glycolytic inhibition and stimulation of mitochondrial metabolism with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase. In melanoma cells harboring the BRAFV600E mutation, RARβ activation antagonized the effect of the BRAF inhibitor PLX4032 (vemurafenib). Collectively, these data suggest that RARβ signaling is involved in regulating cellular metabolism in melanoma and may provide a potential target in combination treatment strategies.
Highlights
Melanoma, the most lethal form of skin cancer, causes 50,000 deaths annually with the incidence continuing to increase worldwide
We show that in primary human melanocytes, all-trans retinoic acid induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RARβ led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis
Cells were treated with the RARβ agonist all-trans retinoic acid (ATRA) for 6 days, and the growth response was determined with a crystal violet-based viability assay
Summary
The most lethal form of skin cancer, causes 50,000 deaths annually with the incidence continuing to increase worldwide. During the progression of melanoma, cellular metabolism is reprogrammed, implying a shift from mitochondrial respiration toward aerobic glycolysis, leading to increased glucose consumption and lactic acid www.impactjournals.com/oncotarget production (the Warburg effect) [7]. Several reports based on in vitro and in vivo models of melanoma and clinical studies of melanoma patients have demonstrated a link between activating mutations at codon V600 of BRAF (most commonly BRAFV600E) and aerobic glycolysis [8,9,10]. BRAFV600E inhibition leads to oxidative addiction through induction of PGC1α and increased mitochondrial respiration [11]. Mitochondrial inhibitors have been suggested as useful adjuvants to BRAF-pathway inhibitors to improve the effect or prevent the development of drug resistance [13,14,15]
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