The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation.
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Date
2019-04-25Author
Parzych, K
Saavedra-García, P
Valbuena, GN
Al-Sadah, HA
Robinson, ME
Penfold, L
Kuzeva, DM
Ruiz-Tellez, A
Loaiza, S
Holzmann, V
Caputo, V
Johnson, DC
Kaiser, MF
Karadimitris, A
Lam, EW-F
Chevet, E
Feldhahn, N
Keun, HC
Auner, HW
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
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
Research team
Myeloma Group
Language
eng
Date accepted
2018-12-07
License start date
2019-04
Citation
Oncogene, 2019, 38 (17), pp. 3216 - 3231
Publisher
NATURE PUBLISHING GROUP