title: Elevation of proteasomal substrate levels sensitizes cells to apoptosis induced by inhibition of proteasomal deubiquitinases.
abstract: Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system.
authors.affiliation: Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Peristera
authors.initials: P
authors.lastname: Roboti
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Puumalainen
authors.affiliation: Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.affiliation: Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.affiliation: Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Hult
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: High
authors.affiliation: Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Eileithyia
authors.initials: E
authors.lastname: Swanton
mesh_terms: D017209:Apoptosis; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008970:Molecular Weight; D010881:Piperidones / Q000494:pharmacology; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D049231:Saposins / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C569633:3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one; C483345:PSAP protein, human; D010881:Piperidones; D061988:Proteasome Inhibitors; D049231:Saposins; D025821:Polyubiquitin; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex; D003545:Cysteine