VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.
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Cancer Cell Protein Metabolism Group, Centre for Haematology, Department of Medicine, Imperial College London, London, UK.
Cell Line, Tumor, Humans, Multiple Myeloma, Protein-Serine-Threonine Kinases, Glucose, Glutamine, Nuclear Proteins, Signal Transduction, MAP Kinase Signaling System, Gene Expression, Autophagy, Adenosine Triphosphatases, Proteolysis, MCF-7 Cells, A549 Cells, Valosin Containing Protein, Proteostasis, Nutrients, PC-3 Cells