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Abstract
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.
Highlights
Cancer cells have a heightened dependency on the mechanisms of protein degradation to maintain protein homoeostasis [1]
We found that VCP/p97 mRNA expression across 917 Cell Line Encyclopedia (CCLE) cancer cell lines significantly correlated with 162 Kyoto Encyclopedia of Genes and Genomes (KEGG) terms
VCP/ p97 expression correlated with several processes that are linked to cellular metabolism and are frequently deregulated in cancer, such as ‘mTOR signalling pathway’ and ‘MAPK signalling pathway’ (Supplementary Table 2)
Summary
Cancer cells have a heightened dependency on the mechanisms of protein degradation to maintain protein homoeostasis (proteostasis) [1]. Drugs that disrupt protein breakdown and trigger proteotoxic stress have considerable potential for anticancer therapy [2, 3]. Multiple myeloma (MM) [4]. VCP/ p97 exerts a segregase activity that uses energy derived from ATP hydrolysis to remodel client proteins, and engages in multiple cellu lar processes that include chromosome segregation, DNA repair, endoplasmic reticulum (ER) and Golgi formation, and activation of NF-κB [9,10,11,12,13,14,15,16]. VCP/p97 has been linked to proteasomeindependent handling of protein aggregates and autophagy
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