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Updated: Nov 11, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Advanced bioinformatic analysis and pathway prediction of NSCLC cells upon cisplatin resistance
A K M Nawshad Hossian1, Fatema Tuz Zahra2, Sagun Poudel1
1School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, USA.
Abstract:
This study aims to identify pathway involvement in the development of cisplatin (cis-diamminedichloroplatinum (II); CDDP) resistance in A549 lung cancer (LC) cells by utilizing advanced bioinformatics software. We developed CDDP-resistant A549 (A549/DDP) cells through prolonged incubation with the drug and performed RNA-seq on RNA extracts to determine differential mRNA and miRNA expression between A549/DDP and A549 cells. We analyzed the gene dysregulation with Ingenuity Pathway Analysis (IPA; QIAGEN) software. In contrast to prior research, which relied on the clustering of dysregulated genes to pathways as an indication of pathway activity, we utilized the IPA software for the dynamic evaluation of pathway activity depending on the gene dysregulation levels. We predicted 15 pathways significantly contributing to the chemoresistance, with several of them to have not been previously reported or analyzed in detail. Among them, the PKR signaling, cholesterol biosynthesis, and TEC signaling pathways are included, as well as genes, such as PIK3R3, miR-34c-5p, and MDM2, among others. We also provide a preliminary analysis of SNPs and indels, present exclusively in A549/DDP cells. This study's results provide novel potential mechanisms and molecular targets that can be explored in future studies and assist in improving the understanding of the chemoresistance phenotype.
Insights
This study reveals novel pathways like PKR signaling involved in cisplatin resistance in lung cancer cells. Findings offer new targets to overcome chemoresistance and improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Cisplatin (cis-diamminedichloroplatinum (II); CDDP) is a cornerstone chemotherapy for lung cancer.
- Acquired chemoresistance limits the efficacy of CDDP treatment in A549 lung cancer (LC) cells.
- Understanding the molecular mechanisms of CDDP resistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To identify key biological pathways contributing to CDDP resistance in A549 LC cells.
- To utilize advanced bioinformatics for a dynamic evaluation of pathway activity.
- To uncover novel molecular targets for overcoming CDDP resistance.
Main Methods:
- Development of CDDP-resistant A549 (A549/DDP) cell line through prolonged drug exposure.
- RNA sequencing (RNA-seq) to determine differential mRNA and miRNA expression profiles.
- Ingenuity Pathway Analysis (IPA) for dynamic pathway activity assessment based on gene dysregulation.
Main Results:
- Prediction of 15 significantly enriched pathways involved in chemoresistance.
- Identification of previously unreported pathways, including PKR signaling, cholesterol biosynthesis, and TEC signaling.
- Highlighting key genes (e.g., PIK3R3, MDM2) and miRNAs (e.g., miR-34c-5p) associated with resistance.
- Preliminary analysis of single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) unique to A549/DDP cells.
Conclusions:
- Novel molecular mechanisms and pathways driving CDDP resistance in A549 LC cells were elucidated.
- Identified pathways and molecular players offer potential therapeutic targets for enhancing chemoresistance.
- This study provides a foundation for future research aimed at improving CDDP treatment efficacy in lung cancer.
