Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin.
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.
From the ‡Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan;
Chia-Wei
CW
Hu
§Department of Life Science, National Taiwan University, Taipei 106, Taiwan;
Chia-Lang
CL
Hsu
¶Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei 112, Taiwan;
Yu-Chao
YC
Wang
‖Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan;
Yasushi
Y
Ishihama
**School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan;
Wei-Chi
WC
Ku
¶Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei 112, Taiwan; hsuancheng@ym.edu.tw yukijuan@ntu.edu.tw.
Hsuan-Cheng
HC
Huang
From the ‡Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan; §Department of Life Science, National Taiwan University, Taipei 106, Taiwan; ‡‡Genome and Systems Biology Degree Program, National Taiwan University, Taipei 106, Taiwan; §§Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan hsuancheng@ym.edu.tw yukijuan@ntu.edu.tw.
Hsueh-Fen
HF
Juan
D000818:Animals; D001313:Aurovertins / Q000008:administration & dosage* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008962:Models, Theoretical; D010766:Phosphorylation; D017510:Protein Folding / Q000187:drug effects; D020543:Proteome / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D001313:Aurovertins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D020543:Proteome; C014416:citreoviridin