1. Academic Validation
  2. Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells

Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells

  • JCI Insight. 2019 Feb 21;4(4):e121582. doi: 10.1172/jci.insight.121582.
Qiyin Zhou 1 2 Hua Li 3 Yuanyuan Li 1 Mingjia Tan 3 Shaohua Fan 3 Cong Cao 4 Feilong Meng 4 Ling Zhu 4 Lili Zhao 5 Min-Xin Guan 4 Hongchuan Jin 2 Yi Sun 1 3
Affiliations

Affiliations

  • 1 Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2 Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir RunRun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 3 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA.
  • 4 Institute of Genetics, Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5 Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Abstract

Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of Cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast Cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin 1 (MFN1) by SCFβ-TrCP E3 Ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1. Importantly, MLN4924-induced mitochondrial fusion is independent of cell cycle progression, but confers cellular survival. Mass-spectrometry-based metabolic profiling and mitochondrial functional assays reveal that MLN4924 inhibits the TCA cycle but promotes mitochondrial OXPHOS. MLN4924 also increases glycolysis by activating PKM2 via promoting its tetramerization. Biologically, MLN4924 coupled with the OXPHOS inhibitor metformin, or the glycolysis inhibitor shikonin, significantly inhibits Cancer cell growth both in vitro and in vivo. Together, our study links neddylation modification and energy metabolism, and provides sound strategies for effective combined Cancer therapies.

Keywords

Bioenergetics; Cancer; Cell Biology; Glucose metabolism; Metabolism.

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