Dataset Information

Temporal Phosphoproteome Dynamics Reveals the Role of ATP Synthase Inhibitor Citreoviridin in Gefitinib-resistant Lung Cancer Cells

ABSTRACT: Non-small cell lung cancer is the leading cause of cancer death worldwide. Gefitinib, epidermal growth factor receptor tyrosine kinase inhibitor, is the first-line treatment of NSCLC, however, many patients eventually become resistant and experience progressive disease. Therefore, development of efficient therapeutic agents to overcome resistance is urgent. We previously found that 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. Citreoviridin suppresses mitogen-activated protein kinase/extracellular signal-regulated kinase signaling by site-specific dephosphorylation of HSP90AB1 on Serine 255 in gefitinib non-resistant lung cancer CL1-0 cells and xenograft model. We are curious whether signaling pathways underlying citreoviridin-treated gefitinib-acquired resistant lung cancer cells are different. In this study, we showed that citreoviridin inhibited cell proliferation and anchorage-dependent growth of gefitinib-acquired resistance NCI-H1975 cells with EGFR T790M mutation. Furthermore, we explored the dynamic molecular response by temporal phosphoproteomic approach. We identified 1476 phosphopeptides corresponding to 738 phosphoproteins and quantified 1901 phosphorylation sites. There were 274 phosphosites corresponding to 174 phosphorylated proteins significantly differential expressed. Functional enrichment analysis demonstrated that citreoviridin treatment affected chromatin organization, cell cycle and apoptosis. Interestingly, we found that citreovirdin suppressed cell proliferation by site-specific phosphorylation of topoisomerase on serine 1106. Citreovirdin induced double strands breaks, and then leaded to DNA damage response. The DNA lesions triggered cells to cell cycle arrest at S phase for repairing or apoptosis for cell death. The results indicated that citreoviridin could potentially be a therapeutic agent against gefitinib-resistant NSCLC.

INSTRUMENT(S): LTQ Orbitrap XL

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Cheng-Wei Tang

LAB HEAD: Hsueh-Fen Juan

PROVIDER: PXD010767 | Pride | 2020-08-17

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20151111_human_uniprot-all.fasta	Fasta
	citreoviridin_phosphoproteomics_raw.rar	Other
	citreoviridin_phosphoproteomics_search.rar	Other

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Publications

Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling Network.

Chang Yi-Wen YW Hsu Chia-Lang CL Tang Cheng-Wei CW Chen Xiang-Jun XJ Huang Hsuan-Cheng HC Juan Hsueh-Fen HF

Molecular & cellular proteomics : MCP 20200811 11

The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation ...[more]

PMID: 32788343

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