Journal Article

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

Cinatl, Jindrich, Michaelis, Martin, Mannewitz, Mareike, Sarin, Navin, Engel, Florian, Kalayda, Ganna V., Saafan, Hisham, Frötschl, Roland, Rothweiler, Florian, Ritter, Christoph A., Jaehde, Ulrich

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: A549 Cells / Adenocarcinoma / Alterations / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Ataxia / Ataxia telangiectasia mutated protein / Ataxia Telangiectasia Mutated Proteins - genetics / Ataxia Telangiectasia Mutated Proteins - metabolism / Biology and Life Sciences / Blotting, Western / Cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - pathology / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell cycle / Chemotherapy / Cisplatin / Cisplatin - pharmacology / Complementation / Cyclin-Dependent Kinase Inhibitor p21 - genetics / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Damage / Deoxyribonucleic acid / DNA / DNA adducts / DNA damage / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Fibroblasts / G2 Phase Cell Cycle Checkpoints - drug effects / G2 Phase Cell Cycle Checkpoints - genetics / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / GTP-binding protein / Heat-Shock Proteins - genetics / Heat-Shock Proteins - metabolism / Homology / Humans / Lung cancer / Lung diseases / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / MDM2 protein / Medical equipment / Medicine and Health Sciences / Non-small cell lung carcinoma / p53 Protein / Pharmacy / Physical Sciences / Platinum / Players / Proteins / Proto-Oncogene Proteins c-mdm2 - genetics / Proto-Oncogene Proteins c-mdm2 - metabolism / Research and Analysis Methods / Reverse Transcriptase Polymerase Chain Reaction / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Virology / Xeroderma pigmentosum / XPC protein