In Search of a Cure for Proteostasis-Addicted Cancer: A AAA Target Revealed

Abstract

Tumorigenesis is often associated with an unbalanced protein homeostasis (proteostasis) network, which sensitizes cancer cells to drugs targeting protein quality control (PQC) regulators. In this issue of Cancer Cell, Anderson and colleagues investigated the anti-cancer activity of a new class of inhibitor against a multi-functional ATPase essential for proteostasis maintenance.

Figure 1.. Roles of p97 in the Cellular Protein Quality Control Network

p97 collaborates with the proteasome in degradation of misfolded ER proteins (the ERAD pathway), defective translocation products (ribosome-associated degradation), misfolded mitochondrial outer membrane proteins (mitochondria-associated degradation), and aberrant nuclear proteins (nuclear quality control). In ERAD and mitochondria-associated degradation, p97 uses energy from ATP hydrolysis to extract misfolded proteins out of the membrane and target them for proteasomal degradation. E3, ubiquitin ligase. In the case of ribosome-associated degradation, ribosome-associated p97 may release stalled translation product to facilitate their turnover. In the nucleus, p97 promotes turnover of aberrant nuclear proteins by acting as a chaperone to prevent substrate aggregation.