Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice

GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival and progression. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine activates GCN2, thus...

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Bibliographic Details
Published in:Biomedicines 2023-10, Vol.11 (10), p.2703
Main Authors: Alexander, Eric T, Fahey, Erin, Phanstiel, 4th, Otto, Gilmour, Susan K
Format: Article
Language:English
Subjects:
Amino acid starvation
Amino acids
Arginine
Autophagy
Biosynthesis
Bone marrow
Cell survival
Endoplasmic reticulum
Enzyme inhibitors
Enzymes
GCN2
Kinases
Lymphoma
Macrophages
Melanoma
Metabolism
Metabolites
myeloid derived suppressor cells
Penicillin
Peptides
polyamine blocking therapy
Polyamines
Stromal cells
Suppressor cells
transport inhibitor
Tumor microenvironment
Tumors
α-difluoromethylornithine
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Summary:GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival and progression. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine activates GCN2, thus rewiring metabolism to support tumor cell survival and drive myeloid immunosuppressive function. We sought to determine if the anti-tumor efficacy of a polyamine blocking therapy (PBT) may be mediated by its effect on GCN2. Unlike wild-type mice, PBT treatment in GCN2 knockout mice bearing syngeneic B16.F10 or EG7 tumors resulted in no tumor growth inhibition and no changes in the profile of infiltrating tumor immune cells. Studies with murine bone marrow cell cultures showed that increased polyamine metabolism and subsequent arginine depletion and GCN2 activation played an essential role in the generation and cytoprotective autophagy of myeloid derived suppressor cells (MDSCs) as well as the M2 polarization and survival of macrophages, all of which were inhibited by PBT. In all, our data suggest that polyamine-dependent GCN2 signaling in stromal cells promotes tumor growth and the development of the immunosuppressive tumor microenvironment, and that the PBT anti-tumor effect is mediated, at least in part, by targeting GCN2.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11102703