Proteome and phosphoproteome reveal mechanisms of action of atorvastatin against esophageal squamous cell carcinoma

Yuan, Qiang; Dong, Christopher D.; Ge, Yang; Chen, Xinhuan; Li, Zhenzhen; Li, Xin; Lu, Qingming; Peng, Feng; Wu, Xiangyu; Zhao, Jimin; Liu, Kangdong

doi:10.18632/aging.102402

Cited by 16 publications

(14 citation statements)

References 39 publications

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“…Not only that, but there is a strong interest in reusing metformin to prevent cancer and cancer recurrence ( 22 ). Our recently study indicated atorvastatin, a lipid-lowering drug ( 23 ), and mefloquine, an anti-malarial drug ( 24 ), had a strong inhibitory effects on ESCC proliferation. Here, we screened the FDA-approved drug and found tegaserod maleate could inhibit proliferation of ESCC both in vivo and in vitro .…”

Section: Discussionmentioning

confidence: 99%

Tegaserod Maleate Inhibits Esophageal Squamous Cell Carcinoma Proliferation by Suppressing the Peroxisome Pathway

Wang

Jiang

et al. 2021

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of esophageal cancer (EC). ESCC accounts for 90% of EC. Recurrence after primary treatment is the main reason for poor survival. Therefore, recurrence prevention is a promising strategy for extending the 5-year survival rate. Here, we found tegaserod maleate could inhibit ESCC proliferation both in vivo and in vitro. Proteomics analysis revealed that tegaserod maleate suppressed the peroxisome signaling pathway, in which the key molecules peroxisome membrane protein 11B (PEX11B) and peroxisome membrane protein 13 (PEX13) were downregulated. The immunofluorescence, catalase activity assay, and reactive oxygen species (ROS) confirmed that downregulation of these proteins was related to impaired peroxisome function. Furthermore, we found that PEX11B and PEX13 were highly expressed in ESCC, and knockout of PEX11B and PEX13 further demonstrated the antitumor effect of tegaserod maleate. Importantly, tegaserod maleate repressed ESCC tumor growth in a patient-derived xenograft (PDX) model in vivo. Our findings conclusively demonstrated that tegaserod maleate inhibits the proliferation of ESCC by suppressing the peroxisome pathway.

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Section: Discussionmentioning

confidence: 99%

Tegaserod Maleate Inhibits Esophageal Squamous Cell Carcinoma Proliferation by Suppressing the Peroxisome Pathway

Wang

Jiang

et al. 2021

Front. Oncol.

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“…Liquid chromatography with tandem mass spectrometryLC–MS/MS analysis was performed as previously described ( Chen et al, 2015 ; Yuan et al, 2019 ). Briefly, after the peptides were dissolved using 0.1% formic acid (FA), samples were separated using an EASY-nLC 1000 ultrahigh performance liquid phase system and then subjected to NSI source, followed by Q-Exactive Plus system analysis.…”

Section: Methodsmentioning

confidence: 99%

Integrative Proteomic and Phosphoproteomic Analyses of Granulosa Cells During Follicular Atresia in Porcine

Yang

Liu

Chen

et al. 2021

Front. Cell Dev. Biol.

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Ovarian follicular atresia is a natural physiological process; however, the mechanism is not fully understood. In this study, quantitative proteomic and phosphoproteomic analyses of granulosa cells (GCs) in healthy (H), slightly atretic (SA), and atretic follicles (A) of porcine were performed by TMT labeling, enrichment of phosphopeptides, and liquid chromatography with tandem mass spectrometry (LC–MS/MS) analysis. In total, 6,201 proteins were quantified, and 4,723 phosphorylation sites of 1,760 proteins were quantified. In total, 24 (11 up, 13 down) and 50 (29 up, 21 down) proteins with a fold change (FC) > 5 were identified in H/SA and H/A, respectively. In addition, there were 20 (H/SA, up) and 39 (H/A, up) phosphosites with an FC > 7 that could serve as potential biomarkers for distinguishing different quality categories of follicles. Western blotting and immunofluorescence confirmed the reliability of the proteomic analysis. Some key proteins (e.g., MIF, beta catenin, integrin β2), phosphosites (e.g., S76 of caspase6, S22 and S636 of lamin A/C), pathways (e.g., apoptosis, regulation of actin cytoskeleton pathway), transcription factors (e.g., STAT5A, FOXO1, and BCLAF1), and kinases (e.g., PBK, CDK5, CDK12, and AKT3) involved in the atresia process were revealed via further analysis of the differentially expressed proteins (DEPs) and phosphorylated proteins (DEPPs). Further study showed that mutant caspase6 Ser76 to Ala increased the ratios of cleaved caspase6/caspase6 and cleaved caspase3/caspase3 and dephosphorylation of caspase6 at Ser76 increased cell apoptotic rate, a new potential pathway of follicular atresia. Collectively, the proteomic and phosphoproteomic profiling and functional research in the current study comprehensively analyzed the dynamic changes in protein expression and phosphorylation during follicular atresia and provided some new explanations regarding the regulation of this process.

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“…Each well was then filled with 100 μL of fresh 1× PBS and high-content cell imaging analysis was used to photograph and analyze the number of cells. [18] 2.4 Cell Proliferation Assay KYSE150 (3.0×10 3 cells/well) and KYSE450 (4.0×10 3 cells/well) cells were seeded into a 96-well plate with 100 μL of complete growth medium (10% FBS) containing various concentrations of Arbidol (final concentration 0, 2.5, 5, 10, and 20 μM) and incubated at 37°C and 5% CO 2 for 24 h, 48 h, 72 h and 96h. The cells were fixed with 4% paraformaldehyde at room temperature for 30 min.…”

Section: Cell Toxicity Assaymentioning

confidence: 99%

Arbidol inhibits esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase

Liu

Dong

Yang

et al. 2022

Preprint

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Background: Esophageal cancer has a global impact on human health due to its high incidence and mortality. Therefore, there is an urgent need to develop new drugs to treat or prevent the prominent pathological subtype of esophageal cancer, esophageal squamous cell carcinoma. Based upon a screening of upon a screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of esophageal squamous cell carcinoma in vitro and in vivo. Method: We first conducted a series of cell-based assays and found that Arbidol treatment based assays inhibited the proliferation and colony formation ability of ESCC cells and promoted G1 phase cell cycle arrest. Phospho-proteomics experiments and proteomics experiments and in vitro kinase assays were subsequently performed using cell lysates derived from Arbidol-treated cells in order to identify thecells in order to identify the underlying growth inhibitory mechanism. Finally, a PDX model was used to verify the inhibitory effect of Arbidol in vivo. Finding: Arbidol inhibits proliferation of ESCC in vitro and in vivo through the DNA replication pathway and is associated with the cell cycle. Interpretation: Arbidol is a potential ATR inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of MCM2 at Ser108.

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Proteome and phosphoproteome reveal mechanisms of action of atorvastatin against esophageal squamous cell carcinoma

Cited by 16 publications

References 39 publications

Tegaserod Maleate Inhibits Esophageal Squamous Cell Carcinoma Proliferation by Suppressing the Peroxisome Pathway

Tegaserod Maleate Inhibits Esophageal Squamous Cell Carcinoma Proliferation by Suppressing the Peroxisome Pathway

Integrative Proteomic and Phosphoproteomic Analyses of Granulosa Cells During Follicular Atresia in Porcine

Arbidol inhibits esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase

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