Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Susan Costantini, Francesca Capone, Andrea Polo, Palmina Bagnara, Alfredo Budillon, Susan Costantini, Francesca Capone, Andrea Polo, Palmina Bagnara, Alfredo Budillon

Abstract

Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors.

Keywords: AAA+ ATPase; CB-5083; VCP; cancer; p97; prognostic biomarker.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Molecular structures (PDB code: 5FTK chain A: 21–763 residues) of the VCP monomer (A) and hexamer (B). The N-terminal region is shown in green, N-D1 linker in black, D1 domain in magenta, D1-D2 linker in blue and D2 in cyan. ADP molecules are presented as red spheres.
Figure 2
Figure 2
Protein−protein interaction network obtained using the Ingenuity Pathway tool showing the role of VCP as a hub node in cyan and all the correlated proteins in yellow symbols.
Figure 3
Figure 3
Biological functions of VCP/p97.

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