The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation

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 fo...

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Veröffentlicht in:Oncogene 2019-04, Vol.38 (17), p.3216-3231
Hauptverfasser: Parzych, Katarzyna, Saavedra-García, Paula, Valbuena, Gabriel N., Al-Sadah, Hibah A., Robinson, Mark E., Penfold, Lucy, Kuzeva, Desislava M., Ruiz-Tellez, Angie, Loaiza, Sandra, Holzmann, Viktoria, Caputo, Valentina, Johnson, David C., Kaiser, Martin F., Karadimitris, Anastasios, Lam, Eric W-F, Chevet, Eric, Feldhahn, Niklas, Keun, Hector C., Auner, Holger W.
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Sprache:eng
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Zusammenfassung: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-018-0651-z