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

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Title: The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation
Authors: Parzych, K
Saavedra Garcia, P
Valbuena, G
Alsadah, HAH
Robinson, M
Penfold, L
Kuzeva, D
Ruiz Tellez, A
Loaiza, S
Holzmann, V
Caputo, V
Johnson, DC
Kaiser, MF
Karadimitris, A
Lam, E
Chevet, E
Feldhahn, N
Keun, H
Auner, H
Item Type: Journal Article
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.
Issue Date: 9-Jan-2019
Date of Acceptance: 7-Dec-2018
URI: http://hdl.handle.net/10044/1/66733
DOI: https://dx.doi.org/10.1038/s41388-018-0651-z
ISSN: 0950-9232
Publisher: Springer Nature [academic journals on nature.com]
Start Page: 3216
End Page: 3231
Journal / Book Title: Oncogene
Volume: 38
Copyright Statement: © 2019 The Authors. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Cancer Research UK
Imperial College Healthcare Charity
British Society for Haematology
British Society For Haematology
Royal Embassy Of Saudi Arabia
Breast Cancer Care & Breast Cancer Now
Breast Cancer Care & Breast Cancer Now
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Cancer Research UK
Funder's Grant Number: 15448
141531
33898
33898/startup
DMU337
2007NovPhD16
2012NovemberPhD016
2012MayPR070
MR/N012097/1
12011
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
VALOSIN-CONTAINING PROTEIN
AMINO-ACID DEPRIVATION
AAA-ATPASE CDC48/P97
ELEVATED EXPRESSION
EIF2-ALPHA KINASE
INDUCED AUTOPHAGY
P97
STRESS
ER
DEGRADATION
A549 Cells
Adenosine Triphosphatases
Autophagy
Cell Line, Tumor
Gene Expression
Glucose
Glutamine
Humans
MAP Kinase Signaling System
MCF-7 Cells
Multiple Myeloma
Nuclear Proteins
Nutrients
PC-3 Cells
Protein-Serine-Threonine Kinases
Proteolysis
Proteostasis
Signal Transduction
Valosin Containing Protein
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
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2019-01-09
Appears in Collections:Department of Surgery and Cancer