title: Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer.
abstract: Wingless-type (Wnt) family of secreted glycoproteins is a group of signal molecules implicated in oncogenesis. Abnormal activation of Wnt signal pathway is associated with a variety of human cancers, including non-small cell lung cancer (NSCLC). Wnt antagonists, such as the secreted frizzled-related protein (SFRP) family, Wnt inhibitory factor-1 (WIF-1) and cerberus, inhibit Wnt signal pathway by directly binding to Wnt molecules. Norcantharidin (NCTD) is known to possess anticancer activity but less nephrotoxicity than cantharidin. In this study, we found that NCTD inhibited cell proliferation, induced apoptosis, arrested cell cycle and suppressed cell invasion/migration in vitro. Additionally, Wnt signal pathway transcription was also suppressed. NCTD treatment blocked cytoplasmic translocation of beta-catenin into the nucleus. Alterations of apoptosis-related proteins, such as Bax, cleaved caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic), had been detected. Furthermore, the expression levels of WIF-1 and SFRP1 were significantly increased in NCTD-treated groups compared with negative control (NC) groups. Abnormal methylation was observed in NC groups, while NCTD treatment promoted WIF-1 demethylation. The present study revealed that NCTD activated WIF-1 via promoter demethylation, inhibiting the canonical Wnt signal pathway in NSCLC, which may present a new therapeutic target in vivo.
authors: Department of Anesthesiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Eastern Qingchun Road, Hangzhou, 310016, People's Republic of China, junranxie@163.com.
authors: Junran
authors: J
authors: Xie
authors: Yaping
authors: Y
authors: Zhang
authors: Xuming
authors: X
authors: Hu
authors: Ran
authors: R
authors: Lv
authors: Dongju
authors: D
authors: Xiao
authors: Li
authors: L
authors: Jiang
authors: Qi
authors: Q
authors: Bao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics; D051176:beta Catenin / Q000235:genetics; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019086:Bridged Bicyclo Compounds, Heterocyclic; D053148:Caspase 3; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C485569:WIF1 protein, human; C069741:norcantharidin