Abstract
The major obstacle in the clinical use of the antitumor drug cisplatin is inherent and acquired resistance. Typically, cisplatin resistance is not restricted to a single mechanism demanding for a systems pharmacology approach to understand a whole cell’s reaction to the drug. In this study, the cellular transcriptome of untreated and cisplatin-treated A549 non-small cell lung cancer cells and their cisplatin-resistant sub-line A549rCDDP2000 was screened with a whole genome array for relevant gene candidates. By combining statistical methods with available gene annotations and without a previously defined hypothesis HRas, MAPK14 (p38), CCL2, DOK1 and PTK2B were identified as genes possibly relevant for cisplatin resistance. These and related genes were further validated on transcriptome (qRT-PCR) and proteome (Western blot) level to select candidates contributing to resistance. HRas, p38, CCL2, DOK1, PTK2B and JNK3 were integrated into a model of resistance-associated signalling alterations describing differential gene and protein expression between cisplatin-sensitive and -resistant cells in reaction to cisplatin exposure.
Highlights
Cisplatin is the backbone of treatment of non-small cell lung cancer (NSCLC)
No significant changes were observed on protein level, a slight decrease in HRas expression after exposure to 11 μM and 34 μM cisplatin was detected in A549rCDDP2000 cells (Figure 4)
MAPK14 (p38), a kinase involved in stress response and cell cycle alterations, was induced on mRNA level following cisplatin treatment but only in sensitive cells
Summary
Cisplatin is the backbone of treatment of non-small cell lung cancer (NSCLC). Patients with advanced or metastatic disease receive a cisplatin-based combination therapy if they carry neither an epithelial growth factor receptor (EGFR) nor an anaplastic lymphoma kinase (ALK) mutation [1]. Research has focused on cell signalling, as several pathways seem to play a major role in the development of chemoresistance. Tumour protein p53 (p53) signalling is a key pathway in apoptosis triggered by cisplatin [4] and p53 mutations are often associated with cisplatin resistance [5]. We found that cisplatin-resistant NSCLC cells are less susceptible to the drug-induced G2/M cell cycle arrest and apoptosis as compared to the sensitive counterparts [6]
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