Inhibition of retinoic acid receptor β signaling confers glycolytic dependence and sensitization to dichloroacetate in melanoma cells

被引:11
作者
Abildgaard, Cecilie [1 ]
Dahl, Christina [1 ]
Abdul-Al, Ahmad [1 ]
Christensen, Annette [1 ]
Guldberg, Per [1 ]
机构
[1] Danish Canc Soc, Res Ctr, Copenhagen, Denmark
关键词
melanoma; cancer metabolism; retinoic acid receptor beta; mitochondrial respiration; dichloroacetate; OVERCOME DRUG-RESISTANCE; OXIDATIVE-PHOSPHORYLATION; BRAF(V600E) INHIBITION; PYRUVATE-DEHYDROGENASE; HUMAN MELANOCYTES; IN-VITRO; MITOCHONDRIAL; METABOLISM; EXPRESSION; KINASE;
D O I
10.18632/oncotarget.20476
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (RAR beta) is epigenetically silenced in a large proportion of melanomas, but a link between RAR beta and metabolic rewiring of melanoma has not been established. Here, we show that in primary human melanocytes, all-trans retinoic acid (a RAR beta agonist) induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RAR beta led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis. In melanoma cells, inhibition of RAR beta 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 BRAF(V600E) mutation, RAR beta activation antagonized the effect of the BRAF inhibitor PLX4032 (vemurafenib). Collectively, these data suggest that RAR beta signaling is involved in regulating cellular metabolism in melanoma and may provide a potential target in combination treatment strategies.
引用
收藏
页码:84210 / 84223
页数:14
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