Glutamine Transport and Mitochondrial Metabolism in Cancer Cell Growth

Abstract

The concept that cancer is a metabolic disease is now well acknowledged: many cancer cell types rely mostly on glucose and some amino acids, especially glutamine for energy supply. These findings were corroborated by overexpression of plasma membrane nutrient transporters, such as the glucose transporters (GLUTs) and some amino acid transporters such as ASCT2, LAT1, and ATB0,+, which became promising targets for pharmacological intervention. On the basis of their sodium-dependent transport modes, ASCT2 and ATB0+ have the capacity to sustain glutamine need of cancer cells; while LAT1, which is sodium independent will have the role of providing cancer cells with some amino acids with plausible signaling roles. According to the metabolic reprogramming of many types of cancer cells, glucose is mainly catabolized by aerobic glycolysis in tumors, while the fate of Glutamine is completed at mitochondrial level where the enzyme Glutaminase converts Glutamine to Glutamate. Glutamine rewiring in cancer cells is heterogeneous. For example, Glutamate is converted to α-Ketoglutarate giving rise to a truncated form of Krebs cycle. This reprogrammed pathway leads to the production of ATP mainly at substrate level and regeneration of reducing equivalents needed for cells growth, redox balance, and metabolic energy. Few studies on hypothetical mitochondrial transporter for Glutamine are reported and indirect evidences suggested its presence. Pharmacological compounds able to inhibit Glutamine metabolism may represent novel drugs for cancer treatments. Interestingly, well acknowledged targets for drugs are the Glutamine transporters of plasma membrane and the key enzyme Glutaminase.

Targeting glutamine metabolism and redox state for leukemia therapy

“…Glutamine metabolism contributes to energy production, macromolecular synthesis, and redox homeostasis, and is essential for survival of some cancer cells that have become addicted to glutamine 10,11,26 .…”

Oxidative stress and antioxidants in the pathophysiology of malignant melanoma

“…Studies in different tumors, including melanoma, have demonstrated that L-Gln utilization correlates with: (a) increased mitochondrial glutaminase 2 activity that is dependent on Rho GTPases and NF-kB activity; and (b) oncogenic levels of Myc which induce a transcriptional program that promotes glutaminolysis and trigger cellular addiction to L-Gln as a bioenergetic substrate (Scalise et al, 2017). Tumors with high rates of glutamine uptake and metabolism can behave as glutamine traps, depleting host glutamine stores, producing glutamate rapidly, and resulting in cachexia (Klimberg and McClellan, 1996).…”

miR‐145 inhibits glutamine metabolism through c‐myc/GLS1 pathways in ovarian cancer cells

“…Although glutamine was previously considered to be a non-essential amino acid in normal organisms, it is essential for rapid proliferation and growth of most cancer cells (De Vitto et al, 2016). Glutamine metabolism can provide intermediate metabolites of biosynthesis of macromolecules for TCA pathway and play a 'reinforcing role' in the TCA cycle (Scalise et al, 2017;Akins et al, 2018). In addition, glutamine also participates in the maintenance of cell redox homeostasis (DeBerardinis and Cheng, 2010).…”