Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest

The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have c
The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.
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Metadaten
Author:Navin Sarin, Florian Engel, Ganna V. Kalayda, Mareike Mannewitz, Jindrich Cinatl, Florian Rothweiler, Martin Michaelis, Hisham Saafan, Christoph A. Ritter, Roland Frötschl
URN:urn:nbn:de:hebis:30:3-439851
DOI:http://dx.doi.org/10.1371/journal.pone.0181081
ISSN:1932-6203
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28746345
Parent Title (English):PLoS one
Publisher:PLoS
Place of publication:Lawrence, Kan.
Contributor(s):Aamir Ahmad
Document Type:Article
Language:English
Date of Publication (online):2017/07/31
Date of first Publication:2017/07/26
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/07/31
Volume:12
Issue:(7): e0181081
Pagenumber:26
First Page:1
Last Page:26
Note:
Copyright: © 2017 Sarin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HeBIS PPN:416499236
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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