Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death

  • GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1β, IL-6, IL-2 and IFN-γ from stimulated macrophages and lymphocytes. In contrast, TGF-β1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response.

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Author:Firas Subhi Salah, Matthias Ebbinghaus, Vijaykumar Yogesh Muley, Zhong-Wei Zhou, K. R. D. Al-Saadi, Manuela Pacyna-Gengelbach, Gregory A. O'Sullivan, Heinrich Betz, Rainer KönigGND, Zhao Qi Wang, Rolf Bräuer, Iver Petersen
URN:urn:nbn:de:hebis:30:3-425247
DOI:https://doi.org/10.1038/cddis.2016.93
ISSN:2041-4889
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27124579
Parent Title (English):Cell Death and Disease
Publisher:Nature Publishing Group
Place of publication:London [u.a.]
Document Type:Article
Language:English
Date of Publication (online):2016/12/21
Date of first Publication:2016/04/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/12/21
Volume:7
Issue:e2205
Page Number:11
First Page:1
Last Page:11
Note:
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.
HeBIS-PPN:424819597
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Angeschlossene und kooperierende Institutionen / MPI für Hirnforschung
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0