title: Piperlongumine induces inhibition of the ubiquitin-proteasome system in cancer cells.
abstract: Piperlongumine, a natural product from the plant Piperlongum, has demonstrated selective cytotoxicity to tumor cells and to show anti-tumor activity in animal models [1]. Cytotoxicity of piperlongumine has been attributed to increase in reactive oxygen species (ROS) in cancer cells. We here report that piperlongumine is an inhibitor of the ubiquitin-proteasome system (UPS). Exposure of tumor cells to piperlongumine resulted in accumulation of a reporter substrate known to be rapidly degraded by the proteasome, and of accumulation of ubiquitin conjugated proteins. However, no inhibition of 20S proteolytic activity or 19S deubiquitinating activity was observed at concentrations inducing cytotoxicity. Consistent with previous reports, piperlongumine induced strong ROS activation which correlated closely with UPS inhibition and cytotoxicity. Proteasomal blocking could not be mimicked by agents that induce oxidative stress. Our results suggest that the anti-cancer activity of piperlongumine involves inhibition of the UPS at a pre-proteasomal step, prior to deubiquitination of malfolded protein substrates at the proteasome, and that the previously reported induction of ROS is a consequence of this inhibition.
authors: Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, S-751 85 Uppsala, Sweden.
authors: Malin
authors: M
authors: Jarvius
authors: Mårten
authors: M
authors: Fryknäs
authors: Pädraig
authors: P
authors: D'Arcy
authors: Chao
authors: C
authors: Sun
authors: Linda
authors: L
authors: Rickardson
authors: Joachim
authors: J
authors: Gullbo
authors: Caroline
authors: C
authors: Haglund
authors: Peter
authors: P
authors: Nygren
authors: Stig
authors: S
authors: Linder
authors: Rolf
authors: R
authors: Larsson
mesh_terms: D045744:Cell Line, Tumor; D004148:Dioxolanes / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D025801:Ubiquitin / Q000037:antagonists & inhibitors*; D010881:Piperidones
chemical_list: D004148:Dioxolanes; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D025801:Ubiquitin; C498077:piperlongumine; D010881:Piperidones