Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer

Abstract

Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.

Integrated RNA and metabolite profiling of urine liquid biopsies for prostate cancer biomarker discovery

“…2b). These urinary cell transcriptional profiles are highly consistent with the principle of altered cancer metabolism and current knowledge of prostate cancer disease progression as determined in tissues and other biofluids 16,25 . Taken together, our data suggest that the transcriptional profiles generated from cells residing in urine from PCa patients are likely to originate from cancerous prostate epithelial cells rather than other urinary tract contaminants.…”

“…Notably, alanine, aspartate, and glutamate metabolism, TCA cycle metabolism, pyruvate metabolism, and several amino acid pathway metabolites were identified at higher levels in PCa urine samples compare to normal ( Fig. 4e), consistent with previous tissue-based studies 16,25 .…”

“…Gene set enrichment analysis (GSEA) of tissue RNA-seq data. Gene expression was analyzed in 65 patients using RNA-seq data 25 . Briefly, RPKM values from tumor and matched normal samples from 65 patients were analyzed for differential gene expression between tumor and matched normal using the Bioconductor limma package 61 .…”

“…of cell types, we next established that the gene expression profiles of urine-exfoliated cells represented expression in prostate tissue using RNA-seq data derived from 65 PCa and matched normal prostate tissues 25 . Most of the 110 up-or downregulated genes in urine exfoliated cells (Table 1) agreed with tissue gene expression ( Fig.…”

STAT3‐dependent analysis revealsPDK4as independent predictor of recurrence in prostate cancer

“…Pyruvate also provides carbon for the synthetic pathways of lipids and amino acids, which are interconnected with the TCA cycle (Gray et al , ). Summing up, PCa cells are metabolically characterized by high TCA/OXPHOS activity (Dakubo et al , ; Latonen et al , ; Shao et al , ) and consumption of citrate, glucose, and lactate (Cutruzzolà et al , ), thereby generating energy and “building blocks” for growth and proliferation.…”