Format

Send to

Choose Destination
Oncogene. 2019 Apr;38(17):3216-3231. doi: 10.1038/s41388-018-0651-z. Epub 2019 Jan 9.

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

Author information

1
Cancer Cell Protein Metabolism Group, Centre for Haematology, Department of Medicine, Imperial College London, London, UK.
2
Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
3
Centre for Haematology, Department of Medicine, Imperial College London, London, UK.
4
Division of Molecular Pathfology, Institute of Cancer Research, Sutton, UK.
5
INSERM U1242, Chemistry, Oncogenesis, Stress, Signaling, Université de Rennes 1, Rennes, France.
6
Centre de Lutte Contre le Cancer Eugène Marquis Rennes, Rennes, France.
7
Cancer Cell Protein Metabolism Group, Centre for Haematology, Department of Medicine, Imperial College London, London, UK. holger.auner04@imperial.ac.uk.

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.

PMID:
30626938
DOI:
10.1038/s41388-018-0651-z
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for Spiral, Imperial College Digital Repository
Loading ...
Support Center