Elevation of proteasomal substrate levels sensitizes cells to apoptosis induced by inhibition of proteasomal deubiquitinases

• Published in: PloS one 2014, Vol.9 (10), p.e108839-e108839
• Main Authors: Sun, Chao, Roboti, Peristera, Puumalainen, Marjo-Riitta, Fryknäs, Mårten, Wang, Xin, D'Arcy, Padraig, Hult, Malin, High, Stephen, Linder, Stig, Swanton, Eileithyia
• Format: Article
• Language: English
• Subjects: Amino acids; Apoptosis; Biology and Life Sciences; Cancer; Catalysis; Catalytic activity; Cell death; Chemotherapy; Cysteine - metabolism; Cysteine - pharmacology; Cytoprotection - drug effects; Cytotoxicity; Drugs; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; HCT116 Cells; Heat shock proteins; HeLa Cells; Homeostasis; Humans; Hypotheses; Inhibitors; Life sciences; Medicin och hälsovetenskap; Medicine and Health Sciences; Molecular Weight; Multiple myeloma; Neurodegeneration; Oncology; Pathology; Piperidones - pharmacology; Polypeptides; Polyubiquitin - metabolism; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; Proteasomes; Protein transport; Protein Transport - drug effects; Proteolysis - drug effects; Saposins - metabolism; Substrate inhibition; Substrate Specificity - drug effects; Substrates; Toxicity; Translocation; Tumor cell lines; Tumor cells; Ubiquitin; Ubiquitin-Specific Proteases - antagonists & inhibitors; Ubiquitin-Specific Proteases - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108839

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.