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

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.

Copy number evolution and its relationship with patient outcome—an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial

“…We identified only a low frequency of CNAs to which IMiD response genes map. In conjuncture with published somatic SNV data, results suggest mutation of these genes per se is not the major determinant of acquired resistance to lenalidomide, or other members of this class of agent in MM [12,[14][15][16][33][34][35].…”

Proteasomes and Several Aspects of Their Heterogeneity Relevant to Cancer

“…Interestingly, the molecular mechanisms by which VCP promotes cancer growth, progression and invasion are at least in part associated with stimulation of UPS-mediated degradation of important regulatory proteins including IκB (NFκB inhibitor) (270–272) and p53 (272, 273). Recently, an important role of VCP in maintaining cancer cell homeostasis in conditions of nutrient (glutamine) depletion was reported (274). Inhibition of VCP induces cancer cell growth arrest and apoptosis (272, 273).…”

Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

“…Moreover, amino acid restriction in differentiated cells can be compensated by autophagy, however, this recycling process does not provide new building blocks for growing cells. Proteasomal protein recycling is nevertheless an essential function for cancer cells as illustrated by proteasomal inhibitors and compounds that interfere with protein ubiquitination [ 14 ], which cause apoptosis due to lack of recycling of cell cycle-regulating proteins [ 15 ]. Thus, it stands to reason that there is a significant therapeutic margin between cancer cells and differentiated cells when it comes to curtailing amino acid supply.…”