Downregulation of dihydrolipoyl dehydrogenase by UVA suppresses melanoma progression via triggering oxidative stress and altering energy metabolism

Silvia Yumnam, Min Cheol Kang, Seung Hyun Oh, Hak Cheol Kwon, Jin Chul Kim, Eun Sung Jung, Choong Hwan Lee, Ai Young Lee, Jong Ik Hwang, Sun Yeou Kim

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)77-87
Number of pages11
JournalFree Radical Biology and Medicine
Volume162
DOIs
Publication statusPublished - 2021 Jan

Keywords

  • A375
  • Autophagy
  • Dihydrolipoyl dehydrogenase
  • MNT1
  • Melanoma
  • NAD/NADH
  • ROS
  • UVA

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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