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