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.

The valosin‐containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload

“…Valosin‐containing protein (VCP) contains a structurally conserved N‐domain followed by two copies of the AAA domain (D1 and D2) (Niwa et al ., ; Xia et al ., ). By interacting with adaptor proteins, VCP has been associated with a wide variety of essential cellular pathways comprising of cell cycle control, transcriptional regulation, apoptosis, protein degradation, and cellular stress responses (Buchberger et al ., ; Vekaria et al ., ; Xia et al ., ). We previously demonstrated that VCP protected cardiomyocyte against apoptosis in vitro (Lizano et al ., ).…”

“…The valosin‐containing protein (VCP) (also called Cdc48 in yeast and plants, CDC‐48 in worms, and Ter94 in flies) is a member of the type II AAA (ATPases associated with various cellular activities) ATPase family which is ubiquitously expressed in cells (Xia et al ., ). Increased expression of VCP correlates with cell growth and survival in cancer cells (Yamamoto et al ., ; Tsujimoto et al ., ; Yamamoto et al ., ; Vekaria et al ., ). Specific genetic mutations of VCP are found to be associated with a multisystem degenerative disorder that affects muscle, bone, and/or the central nervous system (Weihl et al ., ), even though the underlying mechanisms are not fully understood.…”

Valosin-containing protein VCP/p97 is essential for the intracellular development of Leishmania and its survival under heat stress

“…VCP is central to multiple essential protein quality control pathways and VCP‐associated mutations in humans have been implicated in a multitude of diseases, including cancer and neurodegeneration (Fessart et al, ; Meyer & Weihl, ; Tang & Xia, ). Thus, VCP/p97 has emerged as an important therapeutic target not only for cancer and neurodegeneration (Anderson et al, ; Chapman, Maksim, de la Cruz, & Clair, ; Vekaria, Home, Weir, Schoenen, & Rao, ) but also for parasitic diseases (Harbut et al, ). A more comprehensive understanding of the function and regulation of VCP in maintaining protein homeostasis in Leishmania, especially under conditions of intracellular stress, would not only increase knowledge of how this parasite responds to stress but also lead to novel therapeutic interventions.…”

“…VCP is central to multiple essential protein quality control pathways and VCP-associated mutations in humans have been implicated in a multitude of diseases, including cancer and neurodegeneration (Fessart et al, 2013;Meyer & Weihl, 2014;. Thus, VCP/p97 has emerged as an important therapeutic target not only for cancer and neurodegeneration (Anderson et al, 2015;Chapman, Maksim, de la Cruz, & Clair, 2015;Vekaria, Home, Weir, Schoenen, & Rao, 2016) but also for parasitic diseases (Harbut et al, 2012). A more comprehen- (Multicell Wisent Inc., Canada) and 5 μg/ml hemin at pH 7.0 and 25°C.…”

HIV Protease Inhibitor Nelfinavir Targets Human DDI2 and Potentiates Proteasome Inhibitor-based Chemotherapy

“…To reduce drug resistance towards PI-based chemotherapy, new proteasome synthesis should be minimized, and several enzymes in the "bounce-back" loop may serve as molecular targets. Very recently, it has been shown that NGLY1 inhibitors potentiate cytotoxicity of PIs 20,21 , and inhibition of VCP/p97 induces cancer cell death [26][27][28] . Moreover, DDI2 deficiency can attenuate the transcriptional activity of NFE2L1 and potentiate cytotoxicity of PIs 29 .…”