Transcriptome analysis reveals PRKCA as a potential therapeutic target for overcoming cisplatin resistance in lung cancer through ferroptosis

Ting Sun; Penghua Zhang; Qingyi Zhang; Binhui Wang; Qitai Zhao; Fenghui Liu; Xiaohua Ma; Chunling Zhao; Xiaolei Zhou; Ruiying Chen; Songyun Ouyang

Heliyon (May 2024)

Transcriptome analysis reveals PRKCA as a potential therapeutic target for overcoming cisplatin resistance in lung cancer through ferroptosis

Ting Sun,
Penghua Zhang,
Qingyi Zhang,
Binhui Wang,
Qitai Zhao,
Fenghui Liu,
Xiaohua Ma,
Chunling Zhao,
Xiaolei Zhou,
Ruiying Chen,
Songyun Ouyang

Affiliations

Ting Sun: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Penghua Zhang: Department of Radiology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Qingyi Zhang: Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Binhui Wang: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
Qitai Zhao: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
Fenghui Liu: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Xiaohua Ma: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Chunling Zhao: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Xiaolei Zhou: Department of Respiratory medicine, Henan Province Chest Hospital, Zhengzhou 450052, Henan, China
Ruiying Chen: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Corresponding author. Department of Respiratory medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
Songyun Ouyang: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Corresponding author. Department of Respiratory medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.

Journal volume & issue: Vol. 10, no. 10
p. e30780

Abstract

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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.

Published in Heliyon

ISSN: 2405-8440 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Science: Science (General); Social Sciences: Social sciences (General)
Website: https://www.cell.com/heliyon/home

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