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Piperlongumine induces inhibition of the ubiquitin-proteasome system in cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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2013 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 431, no 2, p. 117-123Article in journal (Refereed) Published
Abstract [en]

Piperlongumine, a natural product from the plant Piper longum, 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. 

Place, publisher, year, edition, pages
2013. Vol. 431, no 2, p. 117-123
Keyword [en]
Cancer therapy, Apoptosis, Proteasome, Piperlongumine, Oxidative stress
National Category
Natural Sciences Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-197660DOI: 10.1016/j.bbrc.2013.01.017ISI: 000315325300001OAI: oai:DiVA.org:uu-197660DiVA, id: diva2:613884
Note

De tre första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved

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Jarvius, MalinFryknäs, MårtenRickardson, LindaGullbo, JoachimHaglund, CarolineNygren, PeterLarsson, Rolf

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