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

Katarzyna Parzych1, Paula Saavedra-García1, Gabriel N Valbuena2

  • 1Cancer Cell Protein Metabolism Group, Centre for Haematology, Department of Medicine, Imperial College London, London, UK.

Oncogene
|January 11, 2019
PubMed

Insights

The VCP/p97 protein regulates cellular metabolism and protein balance, crucial for cancer cell survival. Its inhibition impacts metabolic processes, highlighting its role alongside GCN2 in maintaining cancer cell homeostasis.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Metabolic Regulation

Background:

  • The protein VCP/p97 is vital for protein degradation and proteostasis.
  • Its role in cancer makes it an attractive therapeutic target.
  • Emerging evidence suggests VCP/p97 also influences cellular metabolism.

Purpose of the Study:

  • To investigate the role of VCP/p97 in regulating cellular metabolism.
  • To explore the interplay between VCP/p97, nutrient availability, and cancer cell homeostasis.

Main Methods:

  • Gene expression analysis across various cancer cell lines and patient-derived multiple myeloma cells.
  • Assessment of VCP/p97 dependency under nutrient-limited conditions (glucose and glutamine).
  • Inhibition of VCP/p97 and observation of its effects on metabolic pathways and amino acid turnover, including the role of GCN2.

Main Results:

  • VCP/p97 expression correlates with metabolic processes in diverse cancer types.
  • Cancer cells exhibit increased VCP/p97 dependence for proteostasis under nutrient deprivation.
  • Glutamine depletion upregulates VCP/p97, while its inhibition disrupts metabolism and amino acid turnover.
  • GCN2 kinase mitigates VCP/p97 inhibition-induced stress and modulates key cellular pathways.

Conclusions:

  • VCP/p97 is a key regulator of cancer cell metabolism and protein homeostasis.
  • An interconnected regulatory axis exists between VCP/p97, GCN2, and nutrient sensing.
  • Targeting VCP/p97 may offer novel therapeutic strategies by disrupting cancer cell metabolic and protein balance.

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