Signaling through alternative Integrated Stress Response pathways compensates for GCN2 loss in a mouse model of soft tissue sarcoma

• Published in: Scientific reports Vol. 5; no. 1; p. 11781
• Main Authors: Lehman, Stacey L., Ryeom, Sandra, Koumenis, Constantinos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-06-2015; Nature Publishing Group
• Subjects: 38/22; 38/23; 38/77; 38/90; 631/67; 631/67/70; 64/60; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Amino acids; Animal models; Animals; Cell survival; Disease Models, Animal; eIF-2 Kinase - metabolism; Eukaryotic Initiation Factor-2 - metabolism; Female; Gene Expression; Genetic engineering; Humanities and Social Sciences; Humans; Initiation factor eIF-2α; Male; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Muscle Neoplasms - genetics; Muscle Neoplasms - metabolism; Muscle Neoplasms - pathology; Nutrient loss; Nutrients; Phosphorylation; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - genetics; Sarcoma; Sarcoma - genetics; Sarcoma - metabolism; Sarcoma - pathology; Science; Signal Transduction; Soft tissue sarcoma; Stress response; Stress, Physiological; Survival; Tissues; Transcription initiation; Translation; Tumor Burden; Tumor cells; Tumorigenesis; Tumors; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep11781

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.