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.
Highlights
Cell division control protein 48 (CDC48), or p97, is a member of the type II AAA+ protein family of ATPases that participates in a diverse array of cellular activities [1,2,3]
The linker region between the D1 and D2 domains has been reported to be important for ATPase activity and asymmetric assembly of p97 [16]. p97 interacts with its ubiquitinated substrates through a diverse array of ubiquitin adapters that contain the ubiquitin-binding domain (UBD), or p97-binding (UBX), or UBX-like (UBX-L) domain
Activation of Unfolded protein response (UPR) induces the phosphorylation of the transmembrane kinase IRE1α, which catalyzes the splicing of X-box-binding protein [1] (XBP1) which, in turn, induces the transcription of HSP40 family members ERdj4 and the endoplasmic reticulum (ER) degradation enhancer, mannosidase alpha-like 1 (EDEM1), a protein required for Endoplasmic reticulum-associated degradation (ERAD) [56]
Summary
Cell division control protein 48 (CDC48), or p97, is a member of the type II AAA+ protein family of ATPases that participates in a diverse array of cellular activities [1,2,3]. The proteotoxic stress phenotype of tumors, in turn, makes them highly dependent on heat shock protein 90 (HSP90) chaperone function to promote protein folding and maturation [35, 37, 38]. Misfolded proteins that cannot be refolded are polyubiquitinated and degraded by the ubiquitin proteasome system [41,42,43].
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