Metabolic Signaling Cascades Prompted by Glutaminolysis in Cancer

Simple Summary Within the last few years, accumulating evidences suggest the involvement of altered metabolisms in human diseases including cancer. Metabolism is defined as the sum of biochemical processes in living organisms that produce and consume energy. Tumor growth requires restructuring of cellular metabolism to meet the increasing demand for building blocks to support the ever-increasing cancer cell numbers. The principle of perturbed metabolism in tumors is known for 50-60 years, it regains greater appreciation within the last few years with the realization that there is interdependency between metabolism and all aspects of cellular function including regulation and control of cell growth. Tumor cells do not need stimulation signals from the surrounding environment to promote cell proliferation; in some cases, the tumor cells can generate their own growth signals. In order to support the continuous tumor cell growth even under stressful conditions, a change in metabolism is necessary to fulfill the continuous demand for energy and building blocks. A better understanding of the relationship between tumor environment and altered cell metabolisms will provide valuable insights to design innovative approaches to limit the supply of energy and macromolecules for the treatment of cancer including melanoma. Aberrant glutamatergic signaling has been implicated in altered metabolic activity and the demand to synthesize biomass in several types of cancer including melanoma. In the last decade, there has been a significant contribution to our understanding of metabolic pathways. An increasing number of studies are now emphasizing the importance of glutamate functioning as a signaling molecule and a building block for cancer progression. To that end, our group has previously illustrated the role of glutamatergic signaling mediated by metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1, is one of the most abundant amino acids in humans and the predominant excitatory neurotransmitter in the central nervous system. Elevated levels of glutaminolytic mitochondrial tricarboxylic acid (TCA) cycle intermediates, especially glutamate, have been reported in numerous cancer cells. Herein, we highlight and critically review metabolic bottlenecks that are prevalent during tumor evolution along with therapeutic implications of limiting glutamate bioavailability in tumors.