Glutamate production from ammonia via glutamate dehydrogenase 2 activity supports cancer cell proliferation under glutamine depletion

Abstract

Cancer cells rapidly consume glutamine as a carbon and nitrogen source to support proliferation, but the cell number continues to increase exponentially after glutamine is nearly depleted from the medium. In contrast, cell proliferation rates are strongly depressed when cells are cultured in glutamine-free medium. How cancer cells survive in response to nutrient limitation and cellular stress remains poorly understood. In addition, rapid glutamine catabolism yields ammonia, which is a potentially toxic metabolite that is secreted into the extracellular space. Here, we show that ammonia can be utilized for glutamate production, leading to cell proliferation under glutamine-depleted conditions. This proliferation requires glutamate dehydrogenase 2, which synthesizes glutamate from ammonia and α-ketoglutarate and is expressed in MCF7 and T47D cells. Our findings provide insight into how cancer cells survive under glutamine deprivation conditions and thus contribute to elucidating the mechanisms of tumor growth.

DRG Neurons Promote Perineural Invasion of Endometrial Cancer via GluR2

“…However, the key drivers of PNI in cancers have still not been identified. Glutamate as one of the essential neurotransmitters in the nervous system also regulates the growth of cancers [15][16]. A study by Rzeski et al demonstrated that glutamate antagonist could decrease motility and invasion of cancer cells [17].…”

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

“…The glutaminase II pathway consists of the glutamine transaminase K (GTK) (or kynurenine aminotransferase I) catalyzed conversion of glutamine to α‐ketoglutaramate (KGM) using a suitable α‐keto acid acceptor (Equation (1)) followed by hydrolysis of KGM to α‐ketoglutarate catalyzed by ω‐amidodicarboxylate amidohydrolase (ω‐amidase) (Equation (2)). This pathway can then act as a source of glutamate via transamination of α‐ketoglutarate by an α‐ketoglutarate‐linked aminotransferase (Equation (3)) or by reductive amination catalyzed by glutamate dehydrogenase (GDH) (Figure C, orange arrow).…”

Whole exome sequencing of circulating cell-free tumor DNA in a follicular thyroid carcinoma patient with lung and bone metastases

“…11 As a common nonsynonymous mutant gene GLUD2, its activity supports cancer cell proliferation under glutamine depletion. 12 Therefore, these gene mutations may be involved in the metastatic process of FTC.…”