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Transcriptome analysis reveals PRKCA as a potential therapeutic target for overcoming cisplatin resistance in lung
Ting Sun1, Penghua Zhang2, Qingyi Zhang3
1Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Abstract:
Cisplatin-based chemotherapy is the current standard care for lung cancer patients; however, drug resistance frequently develops during treatment, thereby limiting therapeutic efficacy.The molecular mechanisms underlying cisplatin resistance remain elusive. In this study, we conducted an analysis of microarray data from the Gene Expression Omnibus (GEO) database under the accession numbers GSE21656, which encompassed expression profiling of cisplatin-resistant H460 (DDP-H460)and the parental cells (H460). Subsequently, we calculated the differentially expressed genes (DEGs) between DDP-H460 and H460. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs demonstrated significant impact on the Rap1, PI3K/AKT and MAPK signaling pathways. Moreover, protein and protein interaction (PPI) network analysis identified PRKCA, DET1, and UBE2N as hub genes that potentially contribute predominantly to cisplatin resistance. Ultimately, PRKCA was selected for validation due to its significant prognostic effect, which predicts unfavorable overall survival and disease-free survival in patients with lung cancer. Network analysis conducted on The Cancer Genome Atlas (TCGA) database revealed a strong gene-level correlation between PRKCA and TP53, CDKN2A, BYR2, TTN, KRAS, and PIK3CA; whereas at the protein level, it exhibited a high correlation with EGFR, Lck, Bcl2, and Syk. The in vitro experiments revealed that PRKCA was upregulated in the cisplatin-resistant A549 cells (DDP-A549), while knockdown of PRKCA increased DDP-A549 apoptosis upon cisplatin treatment. Moreover, we observed that PRKCA knockdown attenuated DDP-A549 proliferation, migration and invasion ability. Western blot analysis demonstrated that PRKCA knockdown downregulated phosphorylation of PI3K expression while upregulated the genes involved in ferroptosis signaling. In summary, our results elucidate the role of PRKCA in acquiring resistance to cisplatin and underscore its potential as a therapeutic target for cisplatin-resistant lung cancer.
Insights
This study identifies PRKCA as a key driver of cisplatin resistance in lung cancer. Targeting PRKCA may overcome drug resistance and improve patient survival, offering a new therapeutic strategy.
Area of Science:
- Molecular Oncology
- Cancer Genomics
- Chemotherapy Resistance
Background:
- Cisplatin is a standard lung cancer treatment, but resistance limits efficacy.
- Mechanisms of cisplatin resistance are not fully understood.
- Identifying novel therapeutic targets is crucial for improving lung cancer treatment outcomes.
Purpose of the Study:
- To investigate the molecular mechanisms of cisplatin resistance in lung cancer.
- To identify key genes and pathways involved in developing cisplatin resistance.
- To evaluate PRKCA as a potential therapeutic target for overcoming cisplatin resistance.
Main Methods:
- Analysis of microarray data (GEO accession GSE21656) to identify differentially expressed genes (DEGs).
- Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.
- Protein-protein interaction (PPI) network analysis, TCGA database analysis, and in vitro experiments (cell culture, Western blot).
Main Results:
- DEGs impacted Rap1, PI3K/AKT, and MAPK signaling pathways.
- PRKCA, DET1, and UBE2N were identified as hub genes; PRKCA showed prognostic significance.
- PRKCA upregulation correlated with cisplatin resistance; PRKCA knockdown enhanced apoptosis and inhibited proliferation, migration, and invasion in resistant cells.
Conclusions:
- PRKCA plays a critical role in the development of cisplatin resistance in lung cancer.
- PRKCA knockdown affects PI3K signaling and ferroptosis pathways.
- PRKCA represents a promising therapeutic target for overcoming cisplatin resistance in lung cancer patients.
