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
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.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-02020889
Contributor : Laurent Jonchère <>
Submitted on : Friday, February 15, 2019 - 2:58:20 PM
Last modification on : Friday, June 14, 2019 - 2:26:26 PM

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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, Nature Publishing Group, 2019, 38 (17), pp.3216-3231. ⟨10.1038/s41388-018-0651-z⟩. ⟨hal-02020889⟩

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