Glutamatergic system components as potential biomarkers and therapeutic targets in cancer in non-neural organs

Abstract

Glutamate is one of the most abundant amino acids in the blood. Besides its role as a neurotransmitter in the brain, it is a key substrate in several metabolic pathways and a primary messenger that acts through its receptors outside the central nervous system (CNS). The two main types of glutamate receptors, ionotropic and metabotropic, are well characterized in CNS and have been recently analyzed for their roles in non-neural organs. Glutamate receptor expression may be particularly important for tumor growth in organs with high concentrations of glutamate and might also influence the propensity of such tumors to set metastases in glutamate-rich organs, such as the liver. The study of glutamate transporters has also acquired relevance in the physiology and pathologies outside the CNS, especially in the field of cancer research. In this review, we address the recent findings about the expression of glutamatergic system components, such as receptors and transporters, their role in the physiology and pathology of cancer in non-neural organs, and their possible use as biomarkers and therapeutic targets.

Keywords: cancer; excitatory amino acid transporter (EAAT); glutamate/cystine antiporter (xCT); ionotropic glutamate receptor (iGluR); metabotropic glutamate receptor (mGluR); non-neural organs.

Figure 1

Classification of glutamate receptors and transporters. The left panel shows iGluR subunits and the respective coding genes. In the middle, the proteins and respective coding genes of mGluR families are shown. The right panel shows glutamate transporters of glutamate efflux and influx. Cys, cystine. This figure was created with BioRender.com.

Figure 2

Distribution of glutamatergic system components in non-neural organs and cells under normal and cancer conditions. Components in red have only been reported under cancer conditions (they could be expressed de novo under cancer conditions or have not been studied under normal conditions). (, –124).

Figure 3

Schematic representation of the influence of glutamatergic system components on reprogrammed metabolism in cancer cells and the effects over processes associated with cancer. Possible actions of known drugs that affect glutamatergic components over different mechanisms involved in the pathophysiology of cancer that are described in the text are shown. Cys, cystine; GSH, Glutathione; GLS, Glutaminase; ASC, Alanine/serine/cysteine transporter; GDH, Glutamate dehydrogenase; α-KG, alpha-ketoglutarate; ROS, reactive oxygen species; TCA, Tricarboxylic acid cycle; GLUT1, Glucose transporter 1; MCT4, Monocarboxylate transporter 4. This figure was created with BioRender.com.

Figure 4

Advances in knowledge on the expression and actions of glutamatergic system components in cancer in non-neural organs have allowed researchers to consider them as potential biomarkers and therapeutic targets for alleviating the effects of cancer therapy.