Kidney-type glutaminase (GLS1) is a biomarker for pathologic diagnosis and prognosis of hepatocellular carcinoma

Abstract

The lack of sensitive and specific biomarkers hinders pathological diagnosis and prognosis for hepatocellular carcinoma (HCC). Since glutaminolysis plays a crucial role in carcinogenesis and progression, we sought to determine if the expression of kidney-type and liver-type glutaminases (GLS1 and GLS2) were informative for pathological diagnosis and prognosis of HCC. We compared the expression of GLS1 and GLS2 in a large set of clinical samples including HCC, normal liver, and other liver diseases. We found that GLS1 was highly expressed in HCC; whereas, expression of GLS2 was mainly confined to non-tumor hepatocytes. The sensitivity and specificity of GLS1 for HCC were 96.51% and 75.21%, respectively. A metabolic switch from GLS2 to GLS1 was observed in a series of tissues representing progressive pathologic states mimicking HCC oncogenic transformation, including normal liver, fibrotic liver, dysplasia nodule, and HCC. We found that high expression of GLS1 and low expression of GLS2 in HCC correlated with survival time of HCC patients. Expression of GLS1 and GLS2 were independent indexes for survival time; however, prognosis was predominantly determined by the level of GLS1 expression. These findings indicate that GLS1 expression is a sensitive and specific biomarker for pathological diagnosis and prognosis of HCC.

An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease

“…As mentioned earlier, glutaminase has tissue-specific isoenzymes: the GLS2 gene, located on chromosome 12, encoding two isoforms with low activity and allosteric regulation, liver-type glutaminase (LGA, short transcript isoform), and glutaminase B (GAB, long transcript isoform), both highly expressed in normal adult liver [74]; on the other hand, the GLS1 gene, located on chromosome 2, encodes two isoforms with high activity and low Km, the kidney-type glutaminase (KGA, long transcript isoform) and the glutaminase C (GAC, short transcript isoform), both mainly expressed in the kidney under normal healthy conditions. Notably, recent evidence highlights that a metabolic switch from the GLS2 to the high activity GLS1 isoenzyme occurs in liver disease [75, 76], consistent with the increased utilization of hepatic glutamine under these circumstances. Other authors have recently described that glutamine seems to provide acid resistance to Escherichia coli through the enzymatic release of basic ammonium ions, allowing survival in a highly acidic environment [77].…”

The role of glutaminase in cancer

“…20,25 Rapidly growing malignant cells have elevated GLS mRNA levels and enhanced GLS expression, 24,[26][27][28] and GLS enzymatic activity correlates with poor disease outcome in patients with liver, lung, colorectal, breast and brain tumours. 24,25,[29][30][31][32] (refer Table 1) However, it is the GAC variant that is a key enzyme for cancer cell growth. 20,28,33,34 It appears that post-translational phosphorylation of GAC at specific regions of the enzyme by different signalling pathways can alter GLS activity.…”

“…In contrast, Ser95 phosphorylation at the GLS N-terminal region leads to decreased GLS activity. 33 The expression levels of GLS2 variants are markedly increased in tumour cells that are well differentiated, and this is associated with a significantly prolonged survival time 24,25,36,37 (Table 1). GLS2 negatively regulates the activity of the phosphoinositide 3-kinase-AKT signalling pathway 38 and Rac1 by mediating p53 function in hepatocellular carcinoma, resulting in the inhibition of migration, invasion and metastasis of cancer cells.…”

The Glutaminase-1 Inhibitor 968 Enhances Dihydroartemisinin-Mediated Antitumor Efficacy in Hepatocellular Carcinoma Cells

“…The compound 968 suppresses GLS1 activity and inhibits proliferation of cancer cells [32, 33]. Our previous studies demonstrate that a kidney type of glutaminase (GLS1) is highly expressed in HCC [34], and glutaminase-specific silencing by siRNA severely disturbs ROS scavenging systems [34]. GLS1 can therefore be used as a good target for HCC therapy [27].…”

“…Our previous study demonstrated that GLS1 is highly expressed in HCC and can be used as a target for effective anticancer therapy [27, 34]. …”