WIF1 can effectively co-regulate pro-apoptotic activity through the combination with DKK1

Cell Signal. 2014 Nov;26(11):2562-72. doi: 10.1016/j.cellsig.2014.07.026. Epub 2014 Jul 30.

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.

Keywords: Angiogenesis; Caspase-3 activity; Cell cycle arrest; Protein–protein interaction; Signaling pathway; WIF1 tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis*
  • Cell Line, Tumor
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Wnt Signaling Pathway*

Substances

  • Adaptor Proteins, Signal Transducing
  • BCL2 protein, human
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • TP53 protein, human
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • WIF1 protein, human
  • MTOR protein, human
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3