ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1606914
This article is part of the Research TopicGenomic Discoveries and Pharmaceutical Development in Urologic Tumors - Volume IIView all 8 articles
Integrative Genomic Analysis Identifies DPP4 Inhibition as a Modulator of FGF17 and PDGFRA Downregulation and PI3K/Akt Pathway Suppression Leading to Apoptosis
Provisionally accepted
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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Prostate cancer (PCa) remains a significant global health challenge despite advancements in treatment strategies. There is a need to explore the molecular heterogeneity of PCa to facilitate the development of personalized treatment approaches. This study investigates the molecular heterogeneity of PCa by combining genomic and transcriptomic data using a systems biology approach. By utilising whole-genome sequencing and differentially expressed genes from "The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD)" patient samples, we identified 357 intersecting genes. From protein-protein interaction network analysis, 22 hub genes were identified as critical regulators associated with PCa prognosis and pathogenesis. Furthermore, these hub genes were subjected to functional and pathway enrichment analysis via gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG). Notably, the PI3K-Akt signalling pathway was significantly enriched with eight of these hub genes, with significant clinical relevance. Dipeptidyl Peptidase 4 (DPP4) emerged as a promising therapeutic target.Further, in vitro assays were performed to investigate and validate the molecular role of DPP4 through pharmacological inhibition using Linagliptin, a selective DPP4 inhibitor. Inhibition of DPP4 led to the induction of apoptosis, G1/S phase cell cycle arrest, and significant suppression of cell proliferation and migration in PC3 and DU145 cell lines. These experiments revealed novel downstream regulatory effects of DPP4, demonstrating that its inhibition results in the transcriptional downregulation of FGF17, PDGFRA, COL4A1, and COL9A2, thereby contributing to the inactivation of the PI3K-Akt signaling pathway. Collectively, these findings highlight DPP4 as a potential therapeutic target for the treatment of PCa.
Keywords: Linagliptin, prostate cancer, Apoptosis, Mutation, DPP4/CD26, PI3K-Akt pathway, PC3, DU145
Received: 06 Apr 2025; Accepted: 30 Jun 2025.
Copyright: © 2025 Chitluri and Isaac. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Arnold Emerson Isaac, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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