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

Abstract

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.

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

“…The glutaminase II pathway may be especially important in rapidly dividing cells that are known to consume glutamine as an important energy source, such as enterocytes [43], lymphocytes [44], and bone cells [45]. Our findings [1,7] (present work) together with the findings of Udupa et al [9] suggest that the glutaminase II pathway is also important in rapidly dividing cancer cells. Interestingly, the glutamine transporter ASCT2 is strongly expressed in highly proliferative cells, including cancer cells [41,42].…”

“…A recent tracer study with N 15 -and C 13 -labeled glutamine showed that the glutaminase II pathway is active in patient-derived pancreatic ductal adenocarcinoma orthotopic tumors implanted in nude mouse pancreas [9]. Evidence was presented that the glutaminase II pathway is upregulated in these cells when GLS1 is inhibited [9]. It was suggested that an inhibitor of the glutaminase II pathway may be clinically effective as an anti-cancer agent [9].…”

“…Evidence was presented that the glutaminase II pathway is upregulated in these cells when GLS1 is inhibited [9]. It was suggested that an inhibitor of the glutaminase II pathway may be clinically effective as an anti-cancer agent [9]. The present work extends our previous work on the glutaminase II pathway in prostate tissue by showing that glutamine transaminase and ω-amidase specific activities are exceptionally high in normal rat prostate and that the glutaminase II pathway may be important for the transfer of α-ketoglutarate as an energy source from supporting stromal cells to cancer cells [1,7].…”

“…Many cancer cells are 'addicted' to glutamine as an anaplerotic source of α-ketoglutarate while at the same time providing nitrogen for the synthesis of key small M r metabolites and DNA (e.g., [9,[18][19][20]). As noted in the abstract, the conversion of l-glutamine to α-ketoglutarate in cancer cells is almost invariably ascribed to the glutaminase I pathway: l-glutamine is hydrolyzed to l-glutamate followed by conversion of l-glutamate to α-ketoglutarate by an aminotransferase (transaminase) or by glutamate dehydrogenase.…”

“…However, as also noted, mammalian tissues possess another pathway by which l-glutamine is converted to α-ketoglutarate, namely the glutaminase II pathway, consisting of a glutamine transaminase coupled to ω-amidase (Equations (1)-(4)). In this context, tracer studies with [ 15 N]glutamate, [2-15 N]glutamine, [5][6][7][8][9][10][11][12][13][14][15] N]glutamine and [2,[5][6][7][8][9][10][11][12][13][14][15] N]glutamine strongly suggest that the glutaminase II pathway plays a prominent role in the metabolism of l-glutamine in humans [21]. Despite this finding, the glutaminase II pathway has been largely overlooked by biochemists and cancer biologists, even though this pathway is ubiquitous in nature [1].…”