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Review
. 2014 Apr;19(4):450-7.
doi: 10.1016/j.drudis.2013.10.008. Epub 2013 Oct 16.

Glutaminase regulation in cancer cells: a druggable chain of events

William P Katt  1 , Richard A Cerione  2
Affiliations
Review

Glutaminase regulation in cancer cells: a druggable chain of events

William P Katt et al. Drug Discov Today. 2014 Apr.

Abstract

Metabolism is the process by which cells convert relatively simple extracellular nutrients into energy and building blocks necessary for their growth and survival. In cancer cells, metabolism is dramatically altered compared with normal cells. These alterations are known as the Warburg effect. One consequence of these changes is cellular addiction to glutamine. Because of this, in recent years the enzyme glutaminase has become a key target for small molecule therapeutic intervention. Like many oncotargets, however, glutaminase has a number of upstream partners that might offer additional druggable targets. This review summarizes the work from the current decade surrounding glutaminase and its regulation, and suggests strategies for therapeutic intervention in relevant cases.

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Figures

Figure 1
Figure 1
Select inhibitors of kidney-type glutaminases. A number of inhibitors of glutaminase are reported in the literature, from the unselective 6-diazo-5-oxy-l-norleucine (DON) to the minimally potent thiourea scaffold and the recently reported 968 and bis-2-(5-phenylacetamido-1,2[SB17],4-thiadiazol-2-yl)ethyl sulfide (BPTES), and their analogs. IC50 data are presented for each inhibitor versus recombinant (recom.) glutaminase or cell systems as available.
Figure 2
Figure 2
Structure of the enzyme glutaminase C (GAC) in its tetrameric form (PDB ID 3UO9). GAC monomers are thought to form inactive dimers initially (red–yellow or green–blue pairs) with enzyme activation being accompanied by transition to a tetramer. BPTES (cyan) is shown in this crystal structure to bind between the two dimers, whereas mutagenesis and docking studies currently suggest that 968 (grey) binds between the N and C termini of two GAC monomers.
Figure 3
Figure 3
Pathways that intersect with glutaminase. Glutaminase, a key metabolic enzyme, is regulated by a number of diverse mechanisms. Proteins (boxes) or microRNAs (ovals) that have recently been demonstrated to impact glutaminase expression or activity levels are shown. Signaling proteins (e.g. protein kinases, transcription factors) predicted to lead to increased expression or activity of glutaminase are colored green, and those predicted to lead to decreased activity or expression are colored red. Abbreviations: PIAS1/3, protein inhibitor of activated STAT1/3; APC/C, anaphase-promoting complex; Cdh, cadherin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; NF-κB, nuclear factor κB; EGFR, epidermal growth factor receptor; Raf, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated[SB18] kinase.
Figure 4
Figure 4
An assortment of small molecules that inhibit positive regulators of glutaminase. A number of well-studied cancer-related genes have recently been linked directly to glutaminase activity, and thus to glutamine metabolism. This provides a host of small molecule agents that might be reasonably expected to inhibit glutamine metabolism in cancer cells. IC50 data are presented for each inhibitor versus recombinant (recom.) proteins or cell systems as available: *data presented in the Supplementary Information Figure 1[SB19]. Abbreviations: DDMP[SB20], ; ERK, extracellular signal-regulated[SB21] kinase; MEK, mitogen-activated protein kinase kinase; NF-κB, nuclear factor κB.
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