title: ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer.
abstract: Purpose:Constitutively active WNT signaling is a hallmark of colorectal cancers and a driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here, we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer.Experimental Design:We used transcriptomic, proteomic, andin situanalyses to identify ADNP expression in colorectal cancer and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketaminein vivoClinical associations were determined in a cohort of 221 human colorectal cancer cases.Results:ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion, and proliferation of colon cancer cells and accelerated tumor growth in xenograftsin vivoTreatment with subnarcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor-bearing animals. In human patients with colon cancer, high ADNP expression was linked to good prognosis.Conclusions:Our findings indicate that ADNP is a tumor suppressor and promising prognostic marker, and that ketamine treatment with ADNP induction is a potential therapeutic approach that may add benefit to current treatment protocols for patients with colorectal cancer.Clin Cancer Res; 23(11); 2769-80. ©2016 AACR.
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Blaj
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bringmann
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Eva Marina
authors.initials: EM
authors.lastname: Schmidt
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Urbischek
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lamprecht
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fröhlich
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Georg J
authors.initials: GJ
authors.lastname: Arnold
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany. david.horst@med.lmu.de.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Horst
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use; D051379:Mice; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D040901:Proteomics; D060449:Wnt Signaling Pathway / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C492178:ADNP protein, human; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D007649:Ketamine