Abstract
The metabolic changes in melanoma cells that are required for tumor metastasis have not been fully elucidated. In this study, we show that the increase in glucose uptake and mitochondrial oxidative phosphorylation confers metastatic ability as a result of aryl hydrocarbon receptor nuclear translocator (ARNT) deficiency. In clinical tissue specimens, increased ARNT, pyruvate dehydrogenase kinase 1 (PDK1), and NAD(P)H quinine oxidoreductase-1 (NQO1) was observed in benign nevi, whereas lower expression was observed in melanoma. The depletion of ARNT dramatically repressed PDK1 and NQO1 expression, which resulted in an increase of ROS levels. The elimination of ROS using N-acetylcysteine (NAC) and inhibition of oxidative phosphorylation using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and rotenone inhibited the ARNT and PDK1 deficiency-induced cell migration and invasion. In addition, ARNT deficiency in tumor cells manipulated the glycolytic pathway through enhancement of the glucose uptake rate, which reduced glucose dependence. Intriguingly, CCCP and NAC dramatically inhibited ARNT and PDK1 deficiency-induced tumor cell extravasation in mouse models. Our work demonstrates that downregulation of ARNT and PDK1 expression serves as a prognosticator, which confers metastatic potential as the metastasizing cells depend on metabolic changes.
Highlights
Melanoma progression occurs as a result of the malignant proliferation of melanocytes that metastasisize, which contains a series of steps including the following: benign precursor lesion formation, dysplastic nevi formation, radial-growth and vertical-growth phase, and metastasis[1]
We further examined the effect of aryl hydrocarbon receptor nuclear translocator (ARNT) deficiency on reactive oxygen species (ROS) production by using the A375 and A2058 cell lines as models since they are known to harbor the BRAF V600E mutation, which is present in approximately 50% of all melanomas[4]
The results demonstrated that downregulation of the ARNT/pyruvate dehydrogenase kinase 1 (PDK1) axis and the increase in ROS may confer tumor cells with the ability to metastasis
Summary
Melanoma progression occurs as a result of the malignant proliferation of melanocytes that metastasisize, which contains a series of steps including the following: benign precursor lesion formation (benign nevus), dysplastic nevi formation, radial-growth and vertical-growth phase, and metastasis[1]. The accumulation of genetic and epigenetic changes including BRAF and NRAS mutations is thought to genetic alteration is found in approximately 50% of all melanomas[4]. Aryl hydrocarbon receptor (AhR), which is a member of the basic helix-loop-helix/PER-. ARNT-SIM (bHLH-PAS) family promotes the tumorigenicity of melanoma[5,6]. Recent reports show that activation of AhR has been associated with resistance to BRAF-inhibitors and tumor dormancy in melanoma[7,8,9]. The aryl hydrocarbon receptor nuclear translocator (ARNT) belongs to the bHLH-PAS family of transcription factors[10]. ARNT interacts with other bHLH/PAS members to drive different cellular functions[11]. The HIF1α/ARNT complex promotes tumor angiogenesis, erythropoiesis and glycolysis[12].
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