title: WIF1 can effectively co-regulate pro-apoptotic activity through the combination with DKK1.
abstract: Wnt inhibitory factor-1 (WIF1) is a conserved lipid-binding protein that interrupts Wnt ligands by interacting with their Frizzled receptors. Thus, they may suppress the activation of the Wnt/β-catenin triggered signaling cascade. Recently, we found that WIF1 can effectively co-regulate pro-apoptotic activity through the combination with Dickkopf-1 (DKK1). The tumor suppressor p53 protein expression was remarkably increased in the WIF1- and DKK1-transfected cells, along with p21. In contrast, expressions of the anti-apoptotic proteins, c-Myc and Bcl-2, were noticeably reduced. In addition, WIF1 and/or DKK1 significantly activated the transcription of p21 and p53, whereas c-Myc and Bcl-2 activities were remarkably reduced. The tumor suppressor WIF1 was also found to be capable of suppressing tumor growth through the inhibition of tumor angiogenesis in the cellular biological/physiological condition through the targeting of the PI3K/Akt/mTOR signaling pathway, while also being recognized as a Wnt antagonist factor in the Wnt cascade. Consistently, WIF1 conspicuously decreased the VEGF-induced phosphorylation of the PI3K/Akt signaling cascade components, including PDK1, mTOR, TSC-2, GSK-3β, and the p70S6K protein. Collectively, our results indicate for the first time that the tumor suppressor WIF1 is involved in angiogenesis and supplies a possible molecular target for the treatment of distinct malignant cancers, as well as several other associated diseases.
authors.affiliation: Department of Obstetrics and Gynecology, Chungnam National University Hospital, 282, Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
authors.forename: Young Bok
authors.initials: YB
authors.lastname: Ko
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Kyungsil
authors.initials: K
authors.lastname: Yoon
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Obstetrics and Gynecology, Chungnam National University Hospital, 282, Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
authors.forename: Yeonah
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Chungnam National University Hospital, 282, Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
authors.forename: Min A
authors.initials: MA
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Chungnam National University Hospital, 282, Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
authors.forename: Jung Bo
authors.initials: JB
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Chungnam National University Hospital, 282, Munhwa-ro, Jung-gu, Daejeon 301-721, Republic of Korea.
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Park
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Electronic address: sbrho@ncc.re.kr.
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000595707:BCL2 protein, human; C501126:DKK1 protein, human; C489427:MYC protein, human; C495901:TP53 protein, human; C485569:WIF1 protein, human; C546842:MTOR protein, human; C000605506:GSK3B protein, human
keywords: Angiogenesis; Caspase-3 activity; Cell cycle arrest; Protein–protein interaction; Signaling pathway; WIF1 tumor suppressor