Tumour-Derived Glutamate: Linking Aberrant Cancer Cell Metabolism to Peripheral Sensory Pain Pathways

Abstract

Background: Chronic pain is a major symptom that develops in cancer patients, most commonly emerging during advanced stages of the disease. The nature of cancer-induced pain is complex, and the efficacy of current therapeutic interventions is restricted by the dose-limiting sideeffects that accompany common centrally targeted analgesics.

Methods: This review focuses on how up-regulated glutamate production and export by the tumour converge at peripheral afferent nerve terminals to transmit nociceptive signals through the transient receptor cation channel, TRPV1, thereby initiating central sensitization in response to peripheral disease-mediated stimuli.

Results: Cancer cells undergo numerous metabolic changes that include increased glutamine catabolism and over-expression of enzymes involved in glutaminolysis, including glutaminase. This mitochondrial enzyme mediates glutaminolysis, producing large pools of intracellular glutamate. Upregulation of the plasma membrane cystine/glutamate antiporter, system xc -, promotes aberrant glutamate release from cancer cells. Increased levels of extracellular glutamate have been associated with the progression of cancer-induced pain and we discuss how this can be mediated by activation of TRPV1.

Conclusion: With a growing population of patients receiving inadequate treatment for intractable pain, new targets need to be considered to better address this largely unmet clinical need for improving their quality of life. A better understanding of the mechanisms that underlie the unique qualities of cancer pain will help to identify novel targets that are able to limit the initiation of pain from a peripheral source-the tumour.

Keywords: Cancer pain; TRPV1; glutamate; glutaminase; system xc.

Fig. (1)

A. Glutamine, the major circulating amino acid, undergoes hydrolytic deamidation through the enzymatic action of glutaminase (GA), producing glutamate and ammonia (NH₃). GA is referred to as phosphate-activated, as the presence of phosphate can up-regulate its activity. B. In cancer cells, glutamine enters the cell through its membrane transporter, ASCT2. It is then metabolized in the mitochondria into glutamate through glutaminolysis, a process mediated by GA, which is converted from an inactive dimer into an active tetramer. Glutamate is subsequently transformed into α-ketoglutarate, which is further metabolized through the TCA cycle to produce pyruvate and NADPH, key cellular energy sources. The high rate of glutamine metabolism leads to excess levels of intracellular glutamate. At the plasma membrane, system x_c^- transports glutamate out of the cell while importing cystine, which is required for glutathione synthesis to maintain redox balance. NH₃, a significant by-product of glutaminolysis, diffuses from the cell.

Fig. (2)

TRPV1 located on peripheral afferent terminals of sensory neurons indirectly responds to increased local levels of extracellular glutamate secreted from the tumour. Glutamate-mediated activation of TRPV1 occurs via metabotropic glutamate receptors of the group I class as well as ionotropic glutamate receptors that integrate downstream signalling kinase-mediated signalling cascades. Protein Kinase C (PKC) and Protein Kinase A (PKA) phosphorylate and therefore sensitize and/or activate TRPV1. Activation of these kinases lies downstream of mGluR-coupled phospholipase C (PLC) activation which promotes the association of anchoring kinase association protein 79/150 (AKAP 79/150) to TRPV1 where it localizes kinase activity proximal to the channel. AKAP 79/150 also tethers to iGluRs which can mediate activity of anchored kinases. This scaffold system also includes adenylyl cyclase (AC) which promotes cAMP production aiding in activation of PKA. PKC also mediates the translocation of cytoplasmic TRPV1 to the plasma membrane in response to stimuli. In addition to glutamate, exogenous, tumour-secreted factors initiate TRPV1 activation through iGluR polyamine recognition sites and danger associated molecular pattern-induced toll-like receptor 4 (TLR4) activation.

Fig. (3)

Overview of peripheral nociception induced by tumour-derived glutamate. Dysregulated cancer cell metabolism promotes glutamine uptake by ASCT2 transporter and production of large intracellular glutamate pools that drive the activity of the cystine/glutamate transporter, xCT to accommodate the intracellular demand for cysteine, the limiting reagent in glutathione synthesis. Upregulation of glutaminase (GA) and system x_c^- increases the extracellular concentration of glutamate that can be perceived by proximal nociceptive terminals that can translate glutamate into a nociceptive signal by integrating the activities of glutamate receptors with TRPV1. These terminals also release glutamate that can act in an autocrine fashion also activating these same glutamate receptors. TRPV1 translocation to these terminals increases in response to peripheral noxious stimuli through the action of NGF in the dorsal root ganglion.