Identification of Mitochondrial-Related Genes as Potential Biomarkers for Docetaxel-Resistant Prostate Cancer
Abstract
Objectives: Prostate cancer (PC) is the most common cancer among men worldwide and a significant cause of cancer-related deaths. Docetaxel (DX), a taxane-based chemotherapeutic agent, was the first treatment to exhibit substantial efficacy in the management of PC. This study aims to demonstrate the mitochondrial genes that are affected by DX in PC using bioinformatics analysis.
Materials and Methods: For bioinformatics analysis, mRNA microarray data from DX-sensitive PC cell lines (DU145) and DX-resistant cell lines (DU145-DR), corresponding to the study GSE36135, were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed and identified using the Transcriptome Analysis Console 4.0 (TAC). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to pinpoint significant genes and biological pathways associated with DX therapy. Additionally, proteinprotein interaction network analysis was conducted to identify critical proteins and interactions within these pathways.
Results: TAC applied criteria of an adjusted p-value <0.05, (false discovery rate-FDR<0.05) and |log2FC| >1.0 to identify DEGs. The analysis revealed the upregulation of 515 genes and the downregulation of 608 genes in DX-treated cells compared to controls. Enrichment analysis of DEGs indicated their involvement in pathways such as metabolic pathways, pathways of neurodegeneration involving multiple diseases, biosynthesis of cofactors, chemical carcinogenesis mediated by reactive oxygen species, valine, leucine, and isoleucine degradation, carbon metabolism, and oxidative phosphorylation. Among these, ALDH4A1, ALDH6A1, ALDH2, PCCB, GLS, GATM, GLS2, IDH2, SUCLG2, ECI2, GLDC, IVD, ALDH7A1, ACACA, ALDH5A1, NDUFS7, PCK2, ARG2, FDXR, and CPT1A were identified as the most significant candidate genes.
Conclusion: This comprehensive bioinformatics analysis sheds light on the molecular mechanisms underlying DX’s action and highlights potential targets for combination therapies, offering promising strategies to enhance treatment efficacy in PC.
Keywords
: Prostate cancer, docetaxel, bioinformatics, gene expression omnibus, gene expression
Ethical Statement
Not applicable. This paper does not involve human or animal subjects
References
- 1. van Dessel LF, van Riet J, Smits M, et al. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact. Nat Commun. 2019;10:5251.
- 2. Le TK, Duong QH, Baylot V, et al. Castration-resistant prostate cancer: from uncovered resistance mechanisms to current treatments. Cancers (Basel). 2023;15:5047.
- 3. Bolek H, Yazgan SC, Yekeduz E, et al. Androgen receptor pathway inhibitors and drug-drug interactions in prostate cancer. ESMO Open. 2024;9:103736.
- 4. Huang J, Lin B, Li B. Anti-androgen receptor therapies in prostate cancer: a brief update and perspective. Front Oncol. 2022;12:865350.
- 5. Yuan X, Cai C, Chen S, et al. Androgen receptor functions in castrationresistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene. 2014;33(22):2815-25.
- 6. Tzang CC, Wu HW, Lou CA, et al. Efficacy and safety of PARP inhibitors in prostate cancer: an umbrella review of systematic reviews and metaanalyses. Crit Rev Oncol Hematol. 2025:104609.
- 7. Abida W, Armenia J, Gopalan A, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol. 2017;2017
- 8. Mitsiades N, Kaochar S. Androgen receptor signaling inhibitors: postchemotherapy, pre-chemotherapy and now in castration-sensitive prostate cancer. Endocr Relat Cancer. 2021;28:T19-T38.
- 9. Sathekge MM, Lawal IO, Bal C, et al. Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study. Lancet Oncol. 2024;25:175-183.
- 10. Iannantuono GM, Chandran E, Floudas CS, et al. Efficacy and safety of PARP inhibitors in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis of clinical trials. Cancer Treat Rev. 2023;120:102623.