Abstract
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.
Highlights
It was shown that gamma-aminobutyric acid type A receptor-associated protein (GABARAP) has a crucial role in the autophagic process through mediating membrane hemifusion and to be involved in the maturation of the autophagosome, a key component of autophagy machinery.[4,5] As autophagy is a fundamental mechanism for most cells, it is not surprising that the gene is ubiquitously expressed
In order to investigate the potential roles of GABARAP in tumor incidence, female GABARAP KO (KO) and wild-type C57BL/ 6J (Wt) mice were treated with DMBA
We found that the level of transforming growth factor beta 1 (TGF)-β1 was significantly reduced in the serum of DMBA-treated KO mice compared with Wt mice (Figure 2g)
Summary
It was shown that GABARAP has a crucial role in the autophagic process through mediating membrane hemifusion and to be involved in the maturation of the autophagosome, a key component of autophagy machinery.[4,5] As autophagy is a fundamental mechanism for most cells, it is not surprising that the gene is ubiquitously expressed. Autophagy is an intracellular pathway for bulk degradation of damaged proteins and organelles within the lysosome/ vacuole to recycle building blocks for biosynthesis and cellular energy under conditions of stress.[10] Its role in cancer is complex and controversial. It may act as a tumor-promoting as well as tumor-suppressive mechanism depending on the cellular context and the genetic background.[11] In particular, there is a close relationship between autophagy and apoptosis and some of the molecular constituents in this interplay have already been identified. It has been proposed that cancer cellassociated autophagy has a key role in subverting anti-tumor immunity.[20]
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