title: A novel sLRP6E1E2 inhibits canonical Wnt signaling, epithelial-to-mesenchymal transition, and induces mitochondria-dependent apoptosis in lung cancer.
abstract: Aberrant activation of the Wnt pathway contributes to human cancer progression. Antagonists that interfere with Wnt ligand/receptor interactions can be useful in cancer treatments. In this study, we evaluated the therapeutic potential of a soluble Wnt receptor decoy in cancer gene therapy. We designed a Wnt antagonist sLRP6E1E2, and generated a replication-incompetent adenovirus (Ad), dE1-k35/sLRP6E1E2, and a replication-competent oncolytic Ad, RdB-k35/sLRP6E1E2, both expressing sLRP6E1E2. sLRP6E1E2 prevented Wnt-mediated stabilization of cytoplasmic β-catenin, decreased Wnt/β-catenin signaling and cell proliferation via the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways. sLRP6E1E2 induced apoptosis, cytochrome c release, and increased cleavage of PARP and caspase-3. sLRP6E1E2 suppressed growth of the human lung tumor xenograft, and reduced motility and invasion of cancer cells. In addition, sLRP6E1E2 upregulated expression of epithelial marker genes, while sLRP6E1E2 downregulated mesenchymal marker genes. Taken together, sLRP6E1E2, by inhibiting interaction between Wnt and its receptor, suppressed Wnt-induced cell proliferation and epithelial-to-mesenchymal transition.
authors.affiliation: Brain Korea 21 Project for Medical Sciences, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Lee
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
authors.forename: Seong Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000235:genetics / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000235:genetics; D060490:Receptors, Wnt / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D034741:RNA, Small Interfering; D060490:Receptors, Wnt; D051820:TCF Transcription Factors; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin