The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation.
Loading...
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-04-25
Date Accepted
2018-12-07
Date Available
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.
Citation
Oncogene, 2019, 38 (17), pp. 3216 - 3231
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0950-9232
eISSN
1476-5594
Collections
Research Team
Myeloma Group