Inadequate fine-tuning of protein synthesis and failure of amino acid homeostasis following inhibition of the ATPase VCP/p97

• Published in: Cell death & disease Vol. 6; no. 12; p. e2031
• Main Authors: Parzych, K, Chinn, T M, Chen, Z, Loaiza, S, Porsch, F, Valbuena, G N, Kleijnen, M F, Karadimitris, A, Gentleman, E, Keun, H C, Auner, H W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2015; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/95; 38; 631/443/319/1557; 631/67/1059; 631/80/82; 631/80/86; 82; 82/58; 82/80; Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - metabolism; Amino Acids - metabolism; Antibodies; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Enzyme Inhibitors - pharmacology; Eukaryotic Initiation Factor-2 - metabolism; Homeostasis - drug effects; Humans; Immunology; Life Sciences; Mechanistic Target of Rapamycin Complex 1; Models, Biological; Multiprotein Complexes - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Original; original-article; Phosphorylation - drug effects; Proteasome Inhibitors - pharmacology; Protein Biosynthesis - drug effects; Protein Phosphatase 1 - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Up-Regulation - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.373

The cellular mechanisms that control protein degradation may constitute a non-oncogenic cancer cell vulnerability and, therefore, a therapeutic target. Although this proposition is supported by the clinical success of proteasome inhibitors in some malignancies, most cancers are resistant to proteasome inhibition. The ATPase valosin-containing protein (VCP; p97) is an essential regulator of protein degradation in multiple pathways and has emerged as a target for cancer therapy. We found that pharmacological depletion of VCP enzymatic activity with mechanistically different inhibitors robustly induced proteotoxic stress in solid cancer and multiple myeloma cells, including cells that were insensitive, adapted, or clinically resistant to proteasome inhibition. VCP inhibition had an impact on two key regulators of protein synthesis, eukaryotic initiation factor 2 α (eIF2 α ) and mechanistic target of rapamycin complex 1 (mTORC1), and attenuated global protein synthesis. However, a block on protein translation that was itself cytotoxic alleviated stress signaling and reduced cell death triggered by VCP inhibition. Some of the proteotoxic effects of VCP depletion depended on the eIF2 α phosphatase, protein phosphatase 1 regulatory subunit 15A (PPP1R15A)/PP1c, but not on mTORC1, although there appeared to be cross-talk between them. Thus, cancer cell death following VCP inhibition was linked to inadequate fine-tuning of protein synthesis and activity of PPP1R15A/PP1c. VCP inhibitors also perturbed intracellular amino acid levels, activated eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4), and enhanced cellular dependence on amino acid supplies, consistent with a failure of amino acid homeostasis. Many of the observed effects of VCP inhibition differed from the effects triggered by proteasome inhibition or by protein misfolding. Thus, depletion of VCP enzymatic activity triggers cancer cell death in part through inadequate regulation of protein synthesis and amino acid metabolism. The data provide novel insights into the maintenance of intracellular proteostasis by VCP and may have implications for the development of anti-cancer therapies.