Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin*

Abstract

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 mitogenactivated protein kinase/extracellular signal-regulated kinase signaling by site-specific dephosphorylation of HSP90AB1 on Serine 255 and provides perspectives in cancer therapeutic strategies. Molecular & Cellular

Comprehensive quantification of the modified proteome reveals oxidative heart damage in mitochondrial heteroplasmy

“…This category contains the two HSP90 isoforms (HSP90AA1 and HSP90AB1), which harbor PTM sites involved in the regulation of the chaperone activity (Mollapour and Neckers, 2012). These isoforms are known to be phosphorylated at Ser263 and Ser255, respectively (Hu et al, 2015; Wang et al, 2017), within the CK2 phosphorylation motif (S-X-X-E) that is crucial for protein activity. In particular, phosphorylation at Ser255 is required for the activation of MAPK/ERK pathway.…”

Introduction to Cancer Systems Biology

“…8,13 Additionally, using homology modeling and docking simulation, aurovertin B and citreoviridin were screened out to inhibit ATP synthase and found to trigger cancer cell death. We proved that citreoviridininduced response network was involved in protein folding by proteomics and phosphoproteomics 5,13 Furthermore, targeting both ectopic ATP synthase and 26s proteasome induces ER stress in breast cancer cells. 20 In vivo study showed that citreoviridin induces alterations in the expression of glucose metabolism-related enzymes in lung cancer.…”

“…The categories of bioinformatics contain many subfields such as sequence analysis, genome annotation, transcriptome and proteome analyses, as well as network biology and dynamic modeling. 5 Both network biology and modeling are important in the study of systems biology. 1 Network biology includes network and pathway analyses which help researchers understand the relationships within metabolic, protein-protein interaction networks and phospho-signaling pathways.…”

“…The cancer systems biology approach is very effective in identifying drug targets, developing novel therapeutics and new indications for existing drugs. [7][8][9][10] In addition to target and drug discovery, cancer systems biology represents a valuable contribution to efforts toward understanding the molecular mechanism of drugs in various cancer types 5,11 and regulation in cancer progression. 4 …”

MCM2-regulated functional networks in lung cancer by multi-dimensional proteomic approach

“…The total number of modification sites is 338,948 on 20,368 proteins, where seventy-three percent are phosphorylation, 15% ubiquitination and 8% acetylation 19 . To date, a global analysis of serine-, threonine-, and tyrosine-phosphorylation has been performed using advanced mass-spectrometric techniques combined with hydroxy acid-modified metal oxide chromatography (HAMMOC) 20 , 21 . HAMMOC is a precise and popular phosphopeptide enrichment method that uses metal oxide chromatography modified with aliphatic hydroxyl acids to reduce the non-specific binding of acidic amino acid for large-scale study of phosphorylated proteins 22 – 24 .…”