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

Journal article


Parzych, K., Saavedra-García, P., Valbuena, G.N., Al-Sadah, H.A., Robinson, M.E., Penfold, L., Kuzeva, D.M., Ruiz-Tellez, A,, Loaiza, S,, Holzmann, V., Caputo Galarce, V., Johnson, D.C., Kaiser, M.F., Karadimitris, A,, Lam, E.W.F, Chevet, E., Feldhahn, N., Keun, H.C. and Auner, H.W. (2019). The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation. Oncogene. 38, p. 3216–3231. https://doi.org/10.1038/s41388-018-0651-z
AuthorsParzych, K., Saavedra-García, P., Valbuena, G.N., Al-Sadah, H.A., Robinson, M.E., Penfold, L., Kuzeva, D.M., Ruiz-Tellez, A,, Loaiza, S,, Holzmann, V., Caputo Galarce, V., Johnson, D.C., Kaiser, M.F., Karadimitris, A,, Lam, E.W.F, Chevet, E., Feldhahn, N., Keun, H.C. and Auner, H.W.
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.

Year2019
JournalOncogene
Journal citation38, p. 3216–3231
PublisherSpringer Nature
ISSN0950-9232
Digital Object Identifier (DOI)https://doi.org/10.1038/s41388-018-0651-z
Publication dates
Print09 Jan 2019
Publication process dates
Accepted07 Dec 2018
Deposited17 Jun 2021
Publisher's version
License
File Access Level
Open
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