Journal Article

A Novel sLRP6E1E2 Inhibits Canonical Wnt Signaling, Epithelial-to-Mesenchymal Transition, and Induces Mitochondria-Dependent Apoptosis in Lung Cancer

Kwon, Young-Guen, Lee, Jung-Sun, Lee, Seong Kyung, Yun, Chae-Ok, Choi, Won-Il, Hur, Man-Wook

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 1-Phosphatidylinositol 3-kinase / Aberration / Adenoviruses / Adenoviruses, Human - genetics / Androgens / Angiogenesis / Animals / Antagonists / Antigens / Apoptosis / Apoptosis - genetics / Apoptosis - physiology / beta Catenin - metabolism / Binding sites / Biochemistry / Biology / Brain research / Breast cancer / Cancer / Cancer genetics / Cancer therapies / Cancer treatment / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Non-Small-Cell Lung - physiopathology / Carcinoma, Non-Small-Cell Lung - therapy / Caspase / Caspase-3 / Cell Line, Tumor / Cell Proliferation / Colorectal cancer / Cytochrome / Cytochrome c / Epithelial-Mesenchymal Transition - genetics / Epithelial-Mesenchymal Transition - physiology / Gene expression / Gene therapy / Genes / Genetic aspects / Genetic Therapy - methods / Genetic Vectors / Health aspects / Humans / Immunoglobulins / Kinases / Laboratory animals / Leukemia / Ligands / Low Density Lipoprotein Receptor-Related Protein-6 - antagonists & inhibitors / Low Density Lipoprotein Receptor-Related Protein-6 - genetics / Low Density Lipoprotein Receptor-Related Protein-6 - physiology / Lung cancer / Lung diseases / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Lung Neoplasms - physiopathology / Lung Neoplasms - therapy / Male / MAP kinase / Medical research / Medicine / Mesenchyme / Mice / Mice, Nude / Mitochondria / Mitochondria - genetics / Mitochondria - physiology / Mitogens / Molecular biology / Morphology / Neoplasm Invasiveness - prevention & control / Oncolysis / Poly(ADP-ribose) polymerase / Protein kinase / Protein kinases / Proteins / Receptors, Wnt - metabolism / Replication / RNA, Small Interfering - genetics / Signal transduction / Signaling / Skin cancer / Stem cells / TCF Transcription Factors - metabolism / Tumors / Wnt protein / Wnt Signaling Pathway - physiology / Wnt3A Protein - metabolism / Xenograft Model Antitumor Assays / Xenografts / β-Catenin