Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy.
Genomic alterations may make cancer cells more dependent than normal cells on mechanisms of proteostasis, including protein folding and degradation. This proposition is the basis for the clinical use of proteasome inhibitors to treat multiple myeloma and mantle cell lymphoma. However, proteasome inhibitors have not proved effective in treating other cancers, and this has called into question the general applicability of this approach. Here, I consider possible explanations for this apparently limited applicability, and discuss whether inhibiting other broadly acting components of the ubiquitin-proteasome system - including ubiquitin-activating enzyme and the AAA-ATPase p97/VCP - might be more generally effective in cancer therapy.
Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena 91107, CA, USA. Deshaies@caltech.edu.
Raymond J
RJ
Deshaies
D000251:Adenosine Triphosphatases / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000378:metabolism / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000627:therapeutic use; D025801:Ubiquitin / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C404942:p97 ATPase; D044764:Ubiquitin-Activating Enzymes