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

Katarzyna Parzych (1) , Paula Saavedra-García (1) , Gabriel N Valbuena (1) , Hibah A Al-Sadah (1) , Mark E Robinson (1) , Lucy Penfold (1) , Desislava M Kuzeva (1) , Angie Ruiz-Tellez (1) , Sandra Loaiza (1) , Viktoria Holzmann (1) , Valentina Caputo (1) , David C Johnson (2) , Martin F Kaiser (2) , Anastasios Karadimitris (1) , Eric W-F Lam (1) , Eric Chevet (3, 4) , Niklas Feldhahn (1) , Hector C Keun (1) , Holger W Auner (1)

1 Imperial College London
2 The institute of cancer research [London]
3 COSS - Chemistry, Oncogenesis, Stress and Signaling
4 CRLCC - CRLCC Eugène Marquis

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.

Domains: Life Sciences [q-bio]; Cancer

Katarzyna Parzych, Paula Saavedra-García, Gabriel N Valbuena, Hibah A Al-Sadah, Mark E Robinson, et al.. The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation. Oncogene, 2019, 38 (17), pp.3216-3231. ⟨10.1038/s41388-018-0651-z⟩. ⟨hal-02020889⟩