The Metabolic Interplay between Cancer and Other Diseases.

Over the past decade, knowledge of cancer metabolism has expanded exponentially and has provided several clinically relevant targets for cancer therapy. Although these current approaches have shown promise, there are very few studies showing how seemingly unrelated metabolic processes in other diseases can readily occur in cancer. Moreover, the striking metabolic overlap between cancer and other diseases such as diabetes, cardiovascular, neurological, obesity, and aging has provided key therapeutic strategies that have even begun to be translated into clinical trials. These promising results necessitate consideration of the interconnected metabolic network while studying the metabolism of cancer. This review article discusses how cancer metabolism is intertwined with systemic metabolism and how knowledge from other diseases can help to broaden therapeutic opportunities for cancer.

Application of metabolomics technologies toward cancer prognosis and therapy.

Altered metabolism is one of the defining features of cancer. Since the discovery of the Warburg effect in 1924, research into the metabolic aspects of cancer has been reinvigorated over the past decade. Metabolomics is an invaluable tool for gaining insights into numerous biochemical processes including those related to cancer metabolism and metabolic aspects of other diseases. The combination of untargeted and targeted metabolomics approaches has greatly facilitated the discovery of many cancer biomarkers with prognostic potential. Using mass spectrometry-based stable isotope-resolved metabolomics (SIRM) with isotopic labeling, a powerful tool used in pathway analysis, researchers have discovered novel cancer metabolic pathways and metabolic targets for therapeutic application. Metabolomics technologies provide invaluable metabolic insights reflecting cancer progression in coordination with genomics and proteomics aspects. The systematic study of metabolite levels in the metabolome and their dynamics within a biological organism has been, in recent years, applied across a wide range of fields. Metabolomics technologies have been applied to both early clinical trials and pre-clinical research in several essential aspects of human health. This chapter will give an overview of metabolomics technologies and their application in the discovery of novel pathways using isotopic labeled and non-labeled metabolomics.

Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer.

The targeting of glutamine metabolism specifically via pharmacological inhibition of glutaminase 1 (GLS1) has been translated into clinical trials as a novel therapy for several cancers. The results, though encouraging, show room for improvement in terms of tumor reduction. In this study, the glutaminase II pathway is found to be upregulated for glutamate production upon GLS1 inhibition in pancreatic tumors. Moreover, genetic suppression of glutamine transaminase K (GTK), a key enzyme of the glutaminase II pathway, leads to the complete inhibition of pancreatic tumorigenesis in vivo unveiling GTK as a new metabolic target for cancer therapy. These results suggest that current trials using GLS1 inhibition as a therapeutic approach targeting glutamine metabolism in cancer should take into account the upregulation of other metabolic pathways that can lead to glutamate production; one such pathway is the glutaminase II pathway via GTK.

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer.

N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.