Glutaminase isoform expression in cancer: Implications for metabolic adaptation and therapy.

Abstract

3078 Background: Glutamine is a critical amino acid involved in various metabolic pathways, particularly in cancers where its importation is significantly elevated via multiple transporters. Glutaminase, the enzyme catalyzing the deamination of glutamine to glutamate, has two isoforms: kidney-glutaminase 1 (GLS1) and liver-glutaminase 2 (GLS2). This study investigates the expression of glutaminase isoforms in cancers originating from tissues with high glutaminase activity—namely, clear renal cell carcinoma (KIRC), chromophobe renal carcinoma (KICH), papillary renal carcinoma (KIRP), hepatocellular carcinoma (LIHC), and glioblastoma (GBM)—to understand the fate of the imported glutamine. Methods: The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource ([TIMER] 2.0), Gene Expression Profiling Interactive Analysis ([GEPIA] 2.0), and the University of Alabama at Birmingham Cancer Data Analysis ([UALCAN]) Portal were used to investigate GLS1 and GLS2 expression. TIMER 2.0 analyzed 533 KIRC (72 normal), 66 KICH (25 normal), 290 KIRP (32 normal), 153 GBM (5 normal), and 371 LIHC (50 normal) samples. GEPIA 2.0 analyzed 523 KIRC (100 normal), 66 KICH (53 normal), 286 KIRP (60 normal), 163 GBM (207 normal), and 369 LIHC (160 normal). UALCAN analyzed 533 KIRC (72 normal), 66 KICH (25 normal), 290 KIRP (32 normal), 153 GBM (5 normal), and 371 LIHC (50 normal) samples. Additionally, datasets from NCBI GEO were used, including GSE15641 (23 normal, 32 KIRC, 6 KICH, and 12 KIRP), GSE7696 (4 normal, 40 GBM), and GSE41804 (20 normal, 20 LIHC). These platforms detected GLS1 expression in KIRC, KICH, KIRP, and GBM and GLS2 in LIHC by comparing tumor and normal samples. Results: GLS1 was significantly downregulated in KIRC, KICH, KIRP, and GBM across TIMER 2.0, GEPIA 2.0, and UALCAN (P < 0.05). GLS2 was also significantly downregulated in LIHC (P < 0.05). NCBI GEO datasets (GSE15641 for kidney cancers, GSE7696 for GBM, and GSE41804 for LIHC) supported these results, showing consistent GLS1 downregulation in KIRC, KICH, KIRP, and GBM, and GLS2 downregulation in LIHC (adjusted P < 0.05; |Log2FC| > 1). Conclusions: The tissue-specific downregulation of glutaminase isoforms—GLS1 in kidney and brain cancers, GLS2 in liver cancer—highlights an adaptive mechanism in cancer cells to limit glutamine deamination and preserve imported glutamine for other metabolic needs. Enhancing the deamination process could deprive cancer cells of essential precursors for nucleotide synthesis, disrupting their growth and survival. These isoforms represent potential diagnostic markers and therapeutic targets.