Targeting p97 to Disrupt Protein Homeostasis in Cancer

Abstract

Cancer cells are addicted to numerous non-oncogenic traits that enable them to thrive. Proteotoxic stress is one such non-oncogenic trait that is experienced by all tumor cells owing to increased genomic abnormalities and the resulting synthesis and accumulation of non-stoichiometric amounts of cellular proteins. This imbalance in the amounts of proteins ultimately culminates in proteotoxic stress. p97, or valosin-containing protein (VCP), is an ATPase whose function is essential to restore protein homeostasis in the cells. Working in concert with the ubiquitin proteasome system, p97 promotes the retrotranslocation from cellular organelles and/or degradation of misfolded proteins. Consequently, p97 inhibition has emerged as a novel therapeutic target in cancer cells, especially those that have a highly secretory phenotype. This review summarizes our current understanding of the function of p97 in maintaining protein homeostasis and its inhibition with small molecule inhibitors as an emerging strategy to target cancer cells.

Keywords: CDC48; ER stress; ERAD; VCP; cancer; p97 inhibitors; proteotoxic stress.

Figure 1

(A) Domain structure, ribbon diagram of p97 hexameric structure (11), and functions of p97 are summarized. (B) Select inhibitors of p97 ATPase. Chemical structures for Eeyarestatin I, DBeQ, NMS-873, ML240, ML241, compound 18, compound 29, and CB-5083. (C) Comparison of IC₅₀ values for shown compounds for p97 in biochemical and cell-based assays as reported in Ref. (–21).