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Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Department of Odontology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
2010 (English)In: Cell death & disease, ISSN 2041-4889, Vol. 1, no 9, e78- p.Article in journal (Refereed) Published
Abstract [en]

Apoptotic cysteine-aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction.

Place, publisher, year, edition, pages
Nature Publishing Group , 2010. Vol. 1, no 9, e78- p.
Keyword [en]
caspase fragmentation, caspase activity, cisplatin-resistance, malignant pleural mesothelioma
National Category
Cell and Molecular Biology
Research subject
URN: urn:nbn:se:umu:diva-40650DOI: 10.1038/cddis.2010.54ISI: 000282361700010PubMedID: 21364680OAI: diva2:404978
Available from: 2011-03-19 Created: 2011-03-03 Last updated: 2011-03-21Bibliographically approved

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Janson, VeronicaJohansson, AndersGrankvist, Kjell
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