Abildgaard Cecilie, Dahl Christina, Abdul-Al Ahmad, Christensen Annette, Guldberg Per
Danish Cancer Society Research Center, Copenhagen, Denmark.
Oncotarget. 2017 Aug 24;8(48):84210-84223. doi: 10.18632/oncotarget.20476. eCollection 2017 Oct 13.
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 BRAF 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.
黑色素瘤进展过程中的代谢失调与代谢途径调节因子的遗传和表观遗传改变密切相关。在大部分黑色素瘤中，视黄酸受体β（RARβ）会发生表观遗传沉默，但RARβ与黑色素瘤代谢重塑之间的联系尚未确立。在此，我们表明，在原代人黑素细胞中，全反式维甲酸（一种RARβ激动剂）诱导生长抑制，并伴有糖酵解和氧化代谢的降低，而选择性抑制RARβ会导致基础糖酵解速率增加以及对糖酵解抑制的敏感性增加。在黑色素瘤细胞中，抑制RARβ会促进较低的线粒体呼吸和较高的糖酵解活性，从而导致能量应激和能量传感器AMP激活的蛋白激酶的激活。这种代谢转变增加了对糖酵解抑制和用丙酮酸脱氢酶激酶抑制剂二氯乙酸刺激线粒体代谢的敏感性。在携带BRAF突变的黑色素瘤细胞中，RARβ激活拮抗了BRAF抑制剂PLX4032（维莫非尼）的作用。总体而言，这些数据表明RARβ信号通路参与调节黑色素瘤中的细胞代谢，并可能在联合治疗策略中提供一个潜在靶点。
