Abstract
Simple SummaryHigh expression levels of glutaminase (GLS1) are reported for several cancers, and correlate with parameters of disease status. GLS1, the rate-limiting enzyme in the glutamine pathway, is involved in DNA/RNA and amino acid synthesis and contributes to other pathways (e.g., TCA cycle). Inhibition of GLS1 has shown anti-tumor activity in both solid tumors and hematological malignancies. The CB-839 agent, a novel GLS1 inhibitor, has been under investigation clinically. GLS1 expression by immunohistochemical (IHC) staining in prostate has not been definitively demonstrated. We present a retrospective study evaluating GLS1 expression utilizing The Cancer Genome Atlas (TCGA) RNA-Seq data and by IHC in formalin-fixed paraffin embedded radical prostatectomy samples. The study showed a significant difference in GLS1 levels between cancer and non-cancer, but fell short as a prognostic marker. As the study cohort was skewed to less aggressive localized prostate cancer, we support further studies that incorporate high-risk and very high-risk localized and metastatic prostate cancers.High Glutaminase (GLS1) expression may have prognostic implications in colorectal and breast cancers; however, high quality data for expression in prostate cancer (PCa) are lacking. The purpose of this study is to investigate the status of GLS1 expression in PCa and correlated expression levels with clinicopathologic parameters. This study was conducted in two phases: an exploratory cohort analyzing RNA-Seq data for GLS1 from The Cancer Genome Atlas (TCGA) data portal (246 PCa samples) and a GLS1 immunohistochemical protein expression cohort utilizing a tissue microarray (TMA) (154 PCa samples; 41 benign samples) for correlation with clinicopathologic parameters. In the TCGA cohort, GLS1 mRNA expression did not show a statistically significant difference in disease-free survival (DFS) but did show a small significant difference in overall survival (OS). In the TMA cohort, there was no correlation between GLS1 expression and stage, Gleason score, DFS and OS. GLS1 expression did not significantly correlate with the clinical outcomes measured; however, GLS1 expression was higher in PCa cells compared to benign epithelium. Future studies are warranted to evaluate expression levels in greater numbers of high-grade and advanced PCa samples to investigate whether there is a rational basis for GLS1 targeted therapy in a subset of patients with prostate cancer.
Highlights
The essential role of dysregulated glucose metabolism, known as “aerobic glycolysis”, in cancer was first discovered by Otto Warburg and colleagues in the 1920s [1,2,3].Glucose and glutamine are essential nutrients for cell growth and survival [4]
GLS1 mRNA expression barely showed a statistically significant difference in overall survival (Figure 1A,B) and did not show a statistically significant difference in disease-free survival; there was a trend toward a worse disease-free survival with high GLS1 expression (Figure 1C,D)
To further analyze GLS1 expression and to validate these findings, we studied a cohort of 154 patients with localized prostate adenocarcinoma and performed GLS1 IHC, an in situ method, to measure GLS1 protein expression in tumor cells and to correlate the expression with a larger number of clinicopathologic parameters
Summary
The essential role of dysregulated glucose metabolism, known as “aerobic glycolysis”, in cancer was first discovered by Otto Warburg and colleagues in the 1920s [1,2,3]. Glucose and glutamine are essential nutrients for cell growth and survival [4]. Glutamine supplies nitrogen for purine and pyrimidine synthesis and nonessential amino acids for protein synthesis through glutaminolysis, which converts glutamine to glutamate by the rate-limiting enzyme, glutaminase (GLS). Metabolic reactions produce alphaketoglutarate that contributes to the tricarboxylic acid (TCA) cycle and energy production in cancer cells through oxidative phosphorylation [5]. Glutaminolysis plays a significant role in the metabolic reprogramming of cancer cell growth and proliferation. It is believed that glutaminolysis is associated with either activation of oncogenes (such as MYC) [6,7] and/or loss of tumor suppressor genes (such as TP53) [8,9]
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