Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 318, Issue 3, Pages C451-C462Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00286.2019
Keywords
cancer; metabolism; multiple myeloma; proteasome; proteostasis
Categories
Funding
- Amgen Europe, Cancer Research UK [C41494/A27988, C41494/A29035, C41494/A15448]
- British Society for Haematology
- Imperial College London National Institute for Health Research-Biomedical Research Centre
- Imperial College London Cancer Research UK Centre
- Imperial Health Charity (The Blood Fund) [FA1819003]
Ask authors/readers for more resources
Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available