Changes in Gene Transcription Underlying the Aberrant Citrate and Choline Metabolism in Human Prostate Cancer Samples

Abstract

Purpose: Low concentrations of citrate and high concentrations of choline-containing compounds (ChoCC) are metabolic characteristics observed by magnetic resonance spectroscopy of prostate cancer tissue. The objective was to investigate the gene expression changes underlying these metabolic aberrations to find regulatory genes with potential for targeted therapies.Experimental design: Fresh frozen samples (n ¼ 133) from 41 patients undergoing radical prostatectomy were included. Histopathologic evaluation was carried out for each sample before a metabolic profile was obtained with high-resolution magic angle spinning (HR-MAS) spectroscopy. Following the HR-MAS, RNA was extracted from the same sample and quality controlled before carrying out microarray gene expression profiling. A partial least square statistical model was used to integrate the data sets to identify genes whose expression show significant covariance with citrate and ChoCC levels.Results: Samples were classified as benign, n ¼ 35; cancer of low grade (Gleason score 6), n ¼ 24; intermediate grade (Gleason score 7), n ¼ 41; or high grade (Gleason score !8), n ¼ 33. RNA quality was high with a mean RNA Integrity Number score of 9.1 (SD 1.2). Gene products predicting significantly a reduced citrate level were acetyl citrate lyase (ACLY, P ¼ 0.003) and m-aconitase (ACON, P < 0.001). The two genes whose expression most closely accompanied the increase in ChoCC were those of phospholipase A2 group VII (PLA2G7, P < 0.001) and choline kinase a (CHKA, P ¼ 0.002).Conclusions: By integrating histologic, transcriptomic, and metabolic data, our study has contributed to an expanded understanding of the mechanisms underlying aberrant citrate and ChoCC levels in prostate cancer.

Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer

“…3A-3C). Accumulation of choline compound was observed in previous prostate cancer studies (17,25), which was in accordance with our findings. Choline is considered as a key metabolite in prostate cancer, the positronlabeled choline analogues have been studied for the visualization screening of prostate cancer detection via positron emission tomography (26,27).…”

“…For example, this combined approach elucidated altered expression of enzymatic lipases reflecting differential lipid metabolism profiles in pancreatic cancer (16). Likewise, metabolomic study of altered citrate and choline-related metabolism in PCa yielded potential aberrantly expressed enzymes for therapeutic targeting (17).…”

Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells

“…Metabolic anomalies in altered forms of flux through key metabolic pathways are primary hallmarks of many malignant tumors including prostate tumors (Bertilsson et al 2012, Costello & Franklin 2012. Most cancer cells fulfill their energy needs primarily via glycolysis, which is regulated by p53, c-Myc, and hypoxia-inducible factor 1a (HIF-1a (HIF1A); Yeung et al 2008).…”

“…Mitochondrial aconitase (aconitase hydratase, EC4.2.1.3; mACON) is regarded as the key enzyme in citrate oxidation in human prostate epithelial cells and its abnormal expression is implicated in tumorigenesis of the prostate (Costello & Franklin 1994, Juang 2004a, Bertilsson et al 2012. The mACON gene is located in chromosome 22q13.2 and its expression in the prostate is regulated by androgen, prolactin, cholesterol, iron, zinc, and p53 (Juang 2004b,c, Juang et al 2004, Feng et al 2005, Tsui et al 2006.…”

Multiple markers for the non-invasive diagnosis and characterisation of prostate cancer

“…A recently published study related metabolomic changes to genomic disturbances in CaP tissue to demonstrate alterations in m-aconitase and acetyl citrate lyase. Phospholipase A2 group VII and choline kinase α were responsible for altered citrate and choline levels, respectively 103 . Other integrative works investigated colorectal cancer 104 , heart failure 105 and other diseases 106,107 .…”