Integrative analysis of transcriptomic and metabolomic profiles reveals enhanced arginine metabolism in androgen-independent prostate cancer cells

Abstract

Background Prostate cancer is a common solid tumor that affects a significant number of men worldwide. Conventional androgen deprivation therapy (ADT) increases the risk of developing castration-resistant prostate cancer (CRPC). Effective clinical management of patients with CRPC is challenging due to the limited understanding. Methods In this study, transcriptomic and metabolomic profiles of androgen-dependent prostate cancer cell line LNCaP and the androgen-independent cells developed from LNCaP cells (LNCaP-ADR) were investigated using RNA-sequencing and LC-MS/MS, respectively. The differentially expressed genes and metabolites were analyzed, and integrative analysis of transcriptomic and metabolomic data was further conducted to obtain a comprehensive understanding of the metabolic characteristics in LNCaP-ADR cells. Quantitative real-time PCR (QPCR) was employed to ascertain the mRNA expression levels of the selected differentially expressed genes. Results The arginine and proline metabolism pathway was identified as a commonly altered pathway at both the transcriptional and metabolic levels. In the LNCaP-ADR cells, significant upregulation was observed for metabolites including 5-Aminopentanoic acid, L-Arginine, L-Glutamic acid, N-Acetyl-L-alanine, and Pyrrole-2-carboxylic acid at the metabolic level. At the transcriptional level, MAOA, ALDH3A2, ALDH2, ARG1, CKMT2, and CNDP1 were found to be significantly upregulated in the LNCaP-ADR cells. Gene set enrichment analysis (GSEA) identified various enriched gene sets in the LNCaP-ADR cells, encompassing inflammatory response, 9plus2 motile cilium, motile cilium, ciliary plasm, cilium or flagellum-dependent cell motility, cilium movement, cilium, response to endoplasmic reticulum stress, PTEN DN.V1 DN, SRC UP.V1 UP, IL15 UP.V1 DN, RB DN.V1 DN, AKT UP MTOR DN.V1 UP, VEGF A UP.V1 UP, and KRAS.LUNG.BREAST UP.V1 UP. Conclusions These findings highlight the substantial association between the arginine and proline metabolism pathway and CRPC, emphasizing the need to prioritize strategies that target dysregulated metabolites and differentially expressed genes as essential interventions in the clinical management of CRPC.

Potential of CDC25 phosphatases in cancer research and treatment: key to precision medicine

“…Serving as a fundamental building block fuelling diverse cellular processes, encompassing the synthesis of nucleotides, amino acids, and fatty acids essential for sustaining the rapid growth and expansion characteristic of malignant cells making the catabolic enzyme glutaminase a valuable target for cancer therapeutics (Cyriac and Lee, 2024). Other profiles that are used for research purposes and hopefully another facet for therapeutic discovery is the lipid profile (Wu Q. et al, 2024) and kynurenine resulting from liver metabolism, demonstrating results with a high precision and specificity using machine learning models (Wu Q. et al, 2024) illuminating other potential targets for cancer treatment or diagnosis by finding enzymes and differentially regulated genes within their respective pathways (Dai et al, 2023). Another subset of metabolomics, volatile organic compound-omics presents another potentially valuable avenue of research using the volatile profile of human exudates or excretions in, for example, bladder cancer marker identification (Carapito et al, 2024).…”