2. Academic Validation
  3. FAM96A is a novel pro-apoptotic tumor suppressor in gastrointestinal stromal tumors

FAM96A is a novel pro-apoptotic tumor suppressor in gastrointestinal stromal tumors

  • Int J Cancer. 2015 Sep 15;137(6):1318-29. doi: 10.1002/ijc.29498.
Bettina Schwamb 1,  Robert Pick 1,  Sara Beatriz Mateus Fernández 1,  Kirsten Völp 1,  Jan Heering 2,  Volker Dötsch 2,  Susanne Bösser 1,  Jennifer Jung 1,  Rasa Beinoraviciute-Kellner 1,  Josephine Wesely 1,  Inka Zörnig 3,  Matthias Hammerschmidt 4,  Matthias Nowak 4,  Roland Penzel 5,  Kurt Zatloukal 6,  Stefan Joos 7,  Ralf Joachim Rieker 8,  Abbas Agaimy 8,  Stephan Söder 8,  K Marie Reid-Lombardo 9,  Michael L Kendrick 9,  Michael R Bardsley 10,  Yujiro Hayashi 10,  David T Asuzu 10,  Sabriya A Syed 10,  Tamas Ordog 10,  Martin Zörnig 1
Affiliations

Affiliations

  • 1 Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, Frankfurt, Germany.
  • 2 Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University, Frankfurt, Germany.
  • 3 Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Im Neuenheimer Feld 305, Heidelberg, Germany.
  • 4 Max-Planck Institute of Immunobiology, Stuebeweg 51, Freiburg, Germany.
  • 5 Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.
  • 6 Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, Graz, a-8036, Austria.
  • 7 Deutsches Krebsforschungszentrum DKFZ (B060), Im Neuenheimer Feld 280, Heidelberg, Germany.
  • 8 Institute for Pathology, University Hospital Erlangen, Krankenhausstrasse 8-10, Erlangen, Germany.
  • 9 Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN.
  • 10 Center for Individualized Medicine and Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, MN.
PMID: 25716227 DOI: 10.1002/ijc.29498
Abstract

The ability to escape Apoptosis is a hallmark of cancer-initiating cells and a key factor of resistance to oncolytic therapy. Here, we identify FAM96A as a ubiquitous, evolutionarily conserved apoptosome-activating protein and investigate its potential pro-apoptotic tumor suppressor function in gastrointestinal stromal tumors (GISTs). Interaction between FAM96A and apoptotic peptidase activating factor 1 (APAF1) was identified in yeast two-hybrid screen and further studied by deletion mutants, glutathione-S-transferase pull-down, co-immunoprecipitation and immunofluorescence. Effects of FAM96A overexpression and knock-down on Apoptosis sensitivity were examined in Cancer cells and zebrafish embryos. Expression of FAM96A in GISTs and histogenetically related cells including interstitial cells of Cajal (ICCs), "fibroblast-like cells" (FLCs) and ICC stem cells (ICC-SCs) was investigated by Northern blotting, reverse transcription-polymerase chain reaction, immunohistochemistry and Western immunoblotting. Tumorigenicity of GIST cells and transformed murine ICC-SCs stably transduced to re-express FAM96A was studied by xeno- and allografting into immunocompromised mice. FAM96A was found to bind APAF1 and to enhance the induction of mitochondrial Apoptosis. FAM96A protein or mRNA was dramatically reduced or lost in 106 of 108 GIST samples representing three independent patient cohorts. Whereas ICCs, ICC-SCs and FLCs, the presumed normal counterparts of GIST, were found to robustly express FAM96A protein and mRNA, FAM96A expression was much reduced in tumorigenic ICC-SCs. Re-expression of FAM96A in GIST cells and transformed ICC-SCs increased Apoptosis sensitivity and diminished tumorigenicity. Our data suggest FAM96A is a novel pro-apoptotic tumor suppressor that is lost during GIST tumorigenesis.

Keywords

FAM96A; GIST; ICC; apoptosis; tumor suppressor.

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