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Int J Cancer. 2015 Sep 15;137(6):1318-29. doi: 10.1002/ijc.29498. Epub 2015 Mar 12.

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

Author information

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.

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

PMID:
25716227
PMCID:
PMC4497860
DOI:
10.1002/ijc.29498
[Indexed for MEDLINE]
Free PMC Article

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