Two Faces of Glutaminase GLS2 in Carcinogenesis

Abstract

In rapidly proliferating cancer cells, glutamine is a major source of energy and building blocks. Increased glutamine uptake and enhanced glutaminolysis are key metabolic features of many cancers. Glutamine is metabolized by glutaminase (GA), which is encoded by two genes: GLS and GLS2. In contrast to isoforms arising from the GLS gene, which clearly act as oncoproteins, the role of GLS2 products in tumorigenesis is far from well understood. While in some cancer types GLS2 is overexpressed and drives cancer development, in some other types it is downregulated and behaves as a tumor suppressor gene. In this review, we describe the essential functions and regulatory mechanisms of human GLS2 and the cellular compartments in which GLS2 has been localized. Furthermore, we present the context-dependent oncogenic and tumor-suppressor properties of GLS2, and delve into the mechanisms underlying these phenomena.

Keywords: apoptosis; epithelial-mesenchymal transition; ferroptosis; glutaminase GLS2; glutamine metabolism; oxidative stress; tumor promoter; tumor suppressor.

Figure 1

Schematic illustration of human glutaminases: (a) The GLS gene and two alternative transcripts and proteins KGA and GAC; (b) The GLS2 gene and two alternative transcripts and proteins GAB and LGA. Introns are depicted as a solid grey line and exons as numbered purple cylinders. Dashed gray lines indicate the exons forming KGA, GAC, GAB, and LGA mRNA transcripts, respectively. Dashed gray arrows indicate KGA, GAC, GAB, and LGA proteins with defined main signature sequences and motifs. Adapted with permission from [13]. 2016, SNCSC. Adapted with permission from [14]. 2015, Elsevier. Created with BioRender.com.

Figure 2

Molecules which regulate GLS2 expression. Based on [39,41,42,43,44,45,46,47,48,49,50,51,52,53,54]. Created with BioRender.com.