Glutamine addiction: a new therapeutic target in cancer

Abstract

Most cancers depend on a high rate of aerobic glycolysis for their continued growth and survival. Paradoxically, some cancer cell lines also display addiction to glutamine despite the fact that glutamine is a nonessential amino acid that can be synthesized from glucose. The high rate of glutamine uptake exhibited by glutamine-dependent cells does not appear to result solely from its role as a nitrogen donor in nucleotide and amino acid biosynthesis. Instead, glutamine plays a required role in the uptake of essential amino acid and in maintaining activation of TOR kinase. Moreover, in many cancer cells, glutamine is the primary mitochondrial substrate and is required to maintain mitochondrial membrane potential and integrity as well as support of the NADPH production needed for redox control and macromolecular synthesis.

Screening and characterization of extracelluar L-asparaginase producing Bacillus subtilis strain hswx88, isolated from Taptapani hotspring of Odisha, India

“…The tumor cells have a compromised ability to generate L-asparagine endogenously, either due to low expression levels of asparagine synthetase [11] or insufficient amount of its substrates, aspartate or glutamine [12] . Because of their dependence on exogenous L-asparagine, the cancerous acute lymphoblastic leukemia cells, but not normal cells, can be starved and eliminated by LAse treatment which depletes the levels of L-asparagine in circulating pools [13] .…”

“…The results of the morphological, biochemical and physiological tests were put into Bergey's Manual of Determinative Bacteriology [19] and bacterial identification software's like PIBwin version 2.0 and ABIS online for accurate identification. The isolate TPS-12 was exposed to temperature range of 40-100°C, pH range of [3][4][5][6][7][8][9][10][11][12] and sodium chloride concentrations range of 2%-10% for evaluation of physiological characteristics. The antibiogram pattern of the isolate TPS-12 was tested for sensitivity against different antibiotic discs (Himedia, Mumbai) viz., erythromycin (15 …”

“…The isolate TPS-12 when exposed to temperature range of 40-100 °C, showed growth in the temperature range of 150-70 °C, while the growth was restricted above and below the above specified range. The isolate TPS-12 when exposed to different pH range (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and tolerance to different concentrations of sodium chloride (2%-10%), exhibited growth at pH range of [5][6][7][8][9][10] and tolerated sodium chloride concentrations 2%-7% respectively. The isolate showed no growth at pH 3 The results of the antibiogram pattern revealed that the isolate TPS-12 was very sensitive to all the tested antibiotics.…”

Glutamine at focus: versatile roles in cancer

“…2). The challenge is to exploit glutamine metabolism and combine it with other potential drugs already registered with the Food and Drug Administration (FDA), including mitochondrial complex I inhibitors (e.g., metformin and phenformin), modulators of autophagy (e.g., chloroquine and hydroxychloroquine), and inflammatory agents (e.g., verinostat) [157]. In fact, the increased glutamine Baddiction^of some cancers has been exploited in the clinic as a way to disrupt the tumor growth.…”

Metabolic Signature Genes Associated with Susceptibility to Pyruvate Kinase, Muscle Type 2 Gene Ablation in Cancer Cells

“…In some cancer cells, glutamine is a major source for replenishing the intermediates of the TCA cycle required by the continual loss of citrate and malate (another source of acetyl-CoA) from the cycle. Therefore, glutamine uptake and oxidation are important factors for the bioenergetics and biomaterial supplies in cancer cells (Le et al, 2012;Wise and Thompson, 2010). Myc stimulates glutamine metabolism by inducing the expression of glutamine metabolism genes, such as the glutamine transporter SLC1A5 and carbamoyl phosphate synthetase II (CAD) genes (Bush et al, 1998;Wise et al, 2008), or by suppressing the expression of the glutaminase (GLS)-targeting miR-23a/b gene (Gao et al, 2009).…”