Yumnam, S. Kang, M.C. Oh, S.H. Kwon, H.C. Kim, J.C. Jung, E.S. Lee, C.H. Lee, A.-Y. Hwang, J.-I. Kim, S.Y. 2024-01-19T15:33:49Z 2024-01-19T15:33:49Z 2022-01-10 2021-01 0891-5849 https://pubs.kist.re.kr/handle/201004/117568 Melanoma, the most severe form of skin cancer, has poor prognosis and is resistant to chemotherapy. Targeting cancer metabolism is a promising approach in cancer therapeutics. Dihydrolipoyl dehydrogenase (DLD) is a mitochondrial enzyme with diaphorase activity. Here we report a pivotal role of DLD in melanoma cell progression and proliferation. Suppression DLD expression by low intensity UVA (125 mJ/cm2) increased intracellular ROS production and decreased mitochondrial membrane potential thereby inducing autophagy cell death which were confirmed by increased LC3BII and decreased p62 expression in melanoma cells. Knockdown of DLD in melanoma cells also showed similar results. More so, suppression of DLD significantly inhibits in vivo melanoma growth and tumor proliferation. In addition, suppression of DLD increased the NAD+/NADH ratio in melanoma cells and also inhibits TCA cycle related metabolites. DLD downregulation markedly increased α-ketoglutarate and decreased succinic acid suggesting that DLD suppression may have decreased TCA cycle downstream metabolites, resulting in the alteration of mitochondrial energy metabolism Thus the downregulation of DLD induced autophagic cell death in melanoma cells and inhibits in vivo tumor growth and proliferation by increasing ROS production and altering energy metabolism. Our findings suggest that DLD plays a pivotal role in melanoma progression and proliferation. ？ 2020 The Author(s) English Elsevier Inc. Downregulation of dihydrolipoyl dehydrogenase by UVA suppresses melanoma progression via triggering oxidative stress and altering energy metabolism Article 10.1016/j.freeradbiomed.2020.11.037 1 Free Radical Biology and Medicine, v.162, pp.77 - 87 Free Radical Biology and Medicine 162 77 87 N scie scopus 000618623800001 2-s2.0-85097468824 Biochemistry & Molecular Biology Endocrinology & Metabolism Biochemistry & Molecular Biology Endocrinology & Metabolism Article 2 oxoglutaric acid autophagy related protein dihydrolipoamide dehydrogenase LC3BII protein nicotinamide adenine dinucleotide reactive oxygen metabolite reduced nicotinamide adenine dinucleotide sequestosome 1 succinic acid unclassified drug dihydrolipoamide dehydrogenase animal experiment animal model animal tissue Article autophagy (cellular) cancer growth cancer inhibition cell proliferation cell viability citric acid cycle controlled study cytotoxicity DLD gene down regulation energy energy metabolism gene knockdown human human cell in vivo study low energy radiation melanoma melanoma cell mitochondrial energy mitochondrial membrane potential mouse nonhuman oxidative stress priority journal protein expression protein function ultraviolet A radiation apoptosis down regulation genetics melanoma oxidation reduction reaction oxidative stress tumor cell line Apoptosis Cell Line, Tumor Dihydrolipoamide Dehydrogenase Down-Regulation Humans Melanoma Oxidation-Reduction Oxidative Stress A375 Autophagy Dihydrolipoyl dehydrogenase Melanoma MNT1 NAD+/NADH ROS UVA