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Depletion of the ER chaperone ENPL-1 sensitizes C. elegans to the anticancer drug cisplatin
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
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2013 (English)In: Worm, ISSN 2162-4046, Vol. 2, no 1, e24059Article in journal (Refereed) Published
Abstract [en]

Cisplatin is an essential chemotherapeutic drug in the treatment of many cancers. Its use, however, is limited by the development of resistance in many tumors. The ability to re-sensitize resistant tumors could significantly strengthen cisplatin therapy in patients. Caenorhabditis elegans is a suitable model for studying the cytoplasmic role of cisplatin in tumor cells. We have previously shown that the ATPase ASNA-1 has similar roles as a factor governing cisplatin sensitivity in mammalian tumor cells and C. elegans. Here we study the endoplasmic reticulum (ER) resident chaperone ENPL-1/GRP94 and find that its depletion makes worms sensitive to cisplatin. Elevated ER stress levels in enpl-1 mutants is the likely cause of this sensitivity because a correlation can be made between cisplatin sensitivity and the high ER stress levels. We also find that asna-1 mutants have elevated unfolded protein response (UPR) activity and that the intrinsically cisplatin resistant wild-type worms become sensitive when ER stress is high. We conclude that enpl-1 is a cisplatin sensitizing factor and suggest that manipulation of its levels or of UPR activity will enhance the effects of cisplatin based cancer therapy.

Place, publisher, year, edition, pages
Landes Bioscience , 2013. Vol. 2, no 1, e24059
Keyword [en]
cisplatin, unfolded protein response, GRP94, asna-1, endoplasmic reticulum stress
National Category
Surgery Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-90974DOI: 10.4161/worm.24059PubMedID: 24058864OAI: oai:DiVA.org:umu-90974DiVA: diva2:732568
Available from: 2014-07-04 Created: 2014-07-04 Last updated: 2016-05-18Bibliographically approved

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Natarajan, BalasubramanianGaur, RahulHemmingsson, OskarKao, GautamNaredi, Peter
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CiteExportLink to record
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