Glutamate, a metabolic biomarker of aggressiveness and a potential therapeutic target for prostate cancer

Abstract

G lutamate is extensively involved in metabolic and oncogenic pathways. Univariate and multivariate analyses showed that serum glutamate levels directly correlated with Gleason score (f6 vs. o8) and primary prostate cancer (PCa) aggressiveness. Compared with Caucasian Americans, serum glutamate levels were higher in African Americans with metastatic castrateresistant PCa than in the patients with primary tumors. Glutamate deprivation or blockade with pharmacological inhibitors of glutamate release or metabotropic glutamate receptor 1 (GRM1) decreased growth, migration and invasion, and induced apoptosis in both androgen-stimulated and androgenindependent PCa cells. Immunohistochemical staining showed GRM1 overexpression in primary or metastatic PCa tissues. These data highlight the potential of glutamate as a biomarker of aggressiveness in primary PCa and target its metabolic and signaling activities for therapeutic interventions.Malignant cells exhibit altered metabolic profiles and bioenergetic needs which reflect the shift from more efficient metabolism of glucose and mitochondrial adenosine triphosphate (ATP) production to aerobic glycolysis, a wasteful glucose consumption leading to increased lactate production and other bioenergetic demands despite accessibility to oxygen. 1 Since metabolic pathways and key metabolites are tissue-specific and different during the multistep process of neoplastic progression, the search for a universal metabolic phenotype or metabolite in cancer is neither fruitful nor rational. Our knowledge of metabolic changes during various stages of prostate carcinogenesis is very limited. Not surprisingly, our options for using metabolites as biomarkers of malignant transformation and progression or therapeutic targets are limited. The prostate gland in the normal and neoplastic state has a distinct and unique reservoir of metabolites, most prominently in terms of production of prostate-specific antigen, polyamines and citrate. 2 In our search for serum metabolic biomarker(s), we were interested in those small molecules or metabolites which are specifically used as bioenergetic substrates or metabolic precursors of major biosynthetic or lipogenic pathways. Using this approach, glutamate appeared to have unique characteristics. Glutamate, as an intermediate metabolite, is actively involved in the tricarboxylic acid cycle and lipogenesis pathways that are biologically relevant in prostate carcinogenesis and castrate-resistant progression. Glutamate is considered a cell signaling molecule in addition to its extensive role in bioenergetics, biosynthetic pathways and maintenance of other amino acids and nucleotide pools. One important characteristic of glutamate is that its level in the systemic circulation is kept within a stable range 3,4 and its abnormal circulatory level reflects pathological conditions or disturbances in metabolic homeostasis as has been shown in our study. 5

Accelerated echo planar J‐resolved spectroscopic imaging in prostate cancer: a pilot validation of non‐linear reconstruction using total variation and maximum entropy

“…Glu is extensively involved in metabolic and oncogenic pathways. Koochekpour showed that serum Glu levels correlated directly with Gleason scores (<6 versus >8) and primary PCa aggressiveness. In our study, decreased Glx ratios were found in cancerous locations, but were not statistically significant.…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…Non-CNS cancers also secrete glutamate in a manner likely mediated by Na + -independent cysteine/glutamate exchangers [125,126] and vesicular glutamate transporters (vGlut) [127]. Clinically, serum glutamate positively correlates with cancer progression and invasiveness [128], and the protumor effects of glutamate appear to be largely mediated by NMDARs. NMDARs have been identified in a wide variety of tumor types and cancer cell lines (Table 2), and, regardless of subunit configuration, NMDAR blockade reduces both cancer cell proliferation and invasiveness across many different cancers [129][130][131][132][133][134][135][136][137].…”

Glutamate Signaling in Benign and Malignant Disorders: Current Status, Future Perspectives, and Therapeutic Implications

“…Furthermore, we have also detected extracellular Glu release in Glu-depleted conditioned media collected from different PCa cell lines (Koochekpour et al , unpublished data). In addition, our descriptive pilot study demonstrated mGluR1a (also known as GRM1a) overexpression in primary and metastatic PCa tissues 31, 32.…”

“…Furthermore, many studies have indicated that mGluRs are the predominant mediators of glutamatergic signaling in cancer. Importantly, mGluR1 was recently found to be overexpressed in human prostate tumors and further, serum Glu levels correlated with primary prostate cancer (PCa) aggressiveness 31, 32. In addition, rodent mGluR1 protein expression has been shown to cause phenotypes associated with cellular transformation in cultured melanocytes 33, 34.…”