Abstract
The tumor microenvironment is characterized by deficiencies in oxygen and nutrients, such as glucose and amino acids. Activation of the GCN2 arm of the Integrated Stress Response (ISR) in response to amino acid deprivation is one mechanism by which tumor cells cope with nutrient stress. GCN2 phosphorylates the alpha subunit of the eukaryotic translation initiation factor eIF2, leading to global downregulation of translation to conserve amino acids and initiation of a transcriptional program through ATF4 to promote recovery from nutrient deprivation. Loss of GCN2 results in decreased tumor cell survival in vitro under amino acid deprivation and attenuated tumor growth in xenograft tumor models. However, it is not known what effects GCN2 loss has on the growth of autochthonous tumors that arise in their native microenvironment. Here, we demonstrate in a genetically engineered mouse model of soft tissue sarcoma that loss of GCN2 has no effect on tumor growth or animal survival. The sarcomas displayed compensatory activation of PERK or phospho-eIF2α independent upregulation of ATF4 in order to maintain ISR signaling, indicating that this pathway is critical for tumorigenesis. These results have important implications for the development and testing of small molecule inhibitors of ISR kinases as cancer therapeutics.
Highlights
Cells have evolved a variety of pathways to combat both intrinsic and extrinsic stressors
To determine if the tumors were undergoing oxygen and nutrient deprivation, hypoxia levels were assessed by performing immunohistochemistry for the hypoxia marker carbonic anhydrase 9 (CA9)
This study demonstrates the role of GCN2 in a genetically engineered mouse model of soft tissue sarcoma
Summary
Cells have evolved a variety of pathways to combat both intrinsic and extrinsic stressors One such pathway is the Integrated Stress Response (ISR), which consists of four kinases that converge on phosphorylation of the eukaryotic translation initiation factor eIF2α in response to a diverse array of stimuli. Translational upregulation of ATF4 leads to activation of a transcriptional program of genes that regulates a variety of processes, including amino acid transport and synthesis, redox balance, and autophagy[6,7]. Both of these outcomes help to promote cell survival under conditions of stress, but prolonged or severe activation of the ISR can lead to apoptosis[1]. The results of PERK loss in GEMMs recapitulate the observations made in xenograft models
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