Biologic impact of proteasome inhibition in multiple myeloma cells--from the aspects of preclinical studies

Abstract

The ubiquitin-proteasome pathway (UPP) is a major protein degradation system that maintains homeostasis of intracellular proteins, involved in DNA repair, cell cycle regulation, cell proliferation, and drug resistance. Since numerous proteins are processed by proteasomes, their inhibition triggers dramatic disruption of protein homeostasis. Consequently, accumulation of polyubiquitinated proteins triggers different types of cellular stress responses, followed by growth arrest and cytotoxicity. Importantly, multiple myeloma (MM) cells are considered to have lower threshold against these stresses than other cell types, which makes these cells sensitive to proteasome inhibitors.

Figure 1. Mechanism of action of proteasome inhibitor-induced MM cell growth inhibition

Proteasome inhibitors upregulate p53 and induce JNK activation, followed by activation of caspases, which further triggers DNA damage (double-strand break) followed by activation of p53. Activated caspase-3 also cleaves DNA-PKcs and ATM/ATR, as well as gp130, resulting in impaired DNA repair and response to IL-6, respectively. Proteasome inhibitors trigger ER stress and induce activation of IRE1α followed by XBP1 splicing, thereby increasing its transcriptional activity. Proteasome inhibitors block inducible canonical NF-κB activity by cytokines/chemokines or cell adhesion. However, it can directly downregulate IκBα and canonical NF-κB activation, as well as non-canonical NF-κB activity by inhibiting proteasome-dependent p100 conversion to p52.