title: Repression of YAP by NCTD disrupts NSCLC progression.
abstract: The efficacy of available lung cancer therapeutic interference is significantly limited by various resistance mechanisms to those drugs. Activation of the oncogene YAP underlying the initiation, progression, and metastasis of lung cancer associates with poor prognosis and confers drug resistance against targeted therapy. In this study, we evaluated the specificity of norcantharidin (NCTD) in repressing YAP to inhibit non-small cell lung carcinoma (NSCLC) progression. Our study revealed that YAP signal pathways were aberrantly activated in lung cancer tissues and cells which rendered more proliferative and invasive phenotypes to human lung cancer cells. We confirmed that NCTD specifically repressed YAP signaling pathway to interfere the YAP-mediated non-small cell lung carcinoma progression and metastasis via arresting cell cycle, enhancing apoptosis and inducing senescence. We also found NCTD-mediated repression of YAP decreased epithelial-to-mesenchymal transition (EMT) and reduced the motile and invasive cellular phenotype in vitro via enhancing E-cadherin and decreasing fibronectin/vimentin. Mechanistic investigations revealed that NCTD transcriptionally downregulated YAP and post-translationally modulated the subcellular redistribution of YAP between nucleus and cytoplasm. Collectively, our results indicated that NCTD is a novel therapeutic drug candidate for NSCLC which specifically and sensitively target YAP signal pathway.
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Guo
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Kaikai
authors.initials: K
authors.lastname: Gong
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Dai
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: XueLin
authors.initials: X
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Binzhou Medical University Hospital, Binzhou 256603, P.R. China.
authors.forename: Sichuan
authors.initials: S
authors.lastname: Xi
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C069741:norcantharidin
keywords: EMT; NCTD; YAP; cell cycle arrest; lung cancer