Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin

Mol Cell Proteomics. 2015 Dec;14(12):3284-98. doi: 10.1074/mcp.M115.051383. Epub 2015 Oct 26.


Citreoviridin, one of toxic mycotoxins derived from fungal species, can suppress lung cancer cell growth by inhibiting the activity of ectopic ATP synthase, but has limited effect on normal cells. However, the mechanism of citreoviridin triggering dynamic molecular responses in cancer cells remains unclear. Here, we performed temporal phosphoproteomics to elucidate the dynamic changes after citreoviridin treatment in cells and xenograft model. We identified a total of 829 phosphoproteins and demonstrated that citreoviridin treatment affects protein folding, cell cycle, and cytoskeleton function. Furthermore, response network constructed by mathematical modeling shows the relationship between the phosphorylated heat shock protein 90 β and mitogen-activated protein kinase signaling pathway. This work describes that citreoviridin suppresses cancer cell growth and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling by site-specific dephosphorylation of HSP90AB1 on Serine 255 and provides perspectives in cancer therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurovertins / administration & dosage*
  • Aurovertins / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • HSP90 Heat-Shock Proteins / chemistry
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Models, Theoretical
  • Phosphorylation
  • Protein Folding / drug effects
  • Proteome / chemistry
  • Proteome / drug effects*
  • Proteome / genetics
  • Xenograft Model Antitumor Assays


  • Aurovertins
  • Enzyme Inhibitors
  • HSP90 Heat-Shock Proteins
  • HSP90AB1 protein, human
  • Proteome
  • citreoviridin