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Abstract

News on: Inhibiting glutaminase in acute myeloid leukemia: Metabolic dependency of selected AML subtypes by Polina Matre et al. Oncotarget. 2016; 7(48): 79722-79735. doi: 10.18632/oncotarget.12944. The fact that cancer cells rewire their metabolism to meet their extreme energetic and biosynthetic needs has long been known, since the seminal studies by Otto Warburg demonstrated that cancer cells heavily rely on glycolysis even in the presence of oxygen, the so-called Warburg effect. However, efforts to therapeutically target the special requirements of cancer cells have only gained traction in the last decades. In particular, beyond glycolysis and the Warburg effect, recent studies have highlighted a very prominent role for glutaminase (GLS) and glutamine metabolism in several types of hematological and solid tumors. Glutaminase is the ratelimiting enzyme in glutaminolysis and it is encoded by two different genes, GLS and GLS2. In turn, each of these encode for two different isoforms, kidney (KGA) and glutaminase C (GAC) for GLS, and liver (LGA) and glutaminase B (GAB) for GLS2. To further complicate the picture, different tissues express different levels of all these isoforms. In the current issue of Oncotarget, Matre et al. [1] comprehensively analyze the expression of GLS and GLUD1 (which catalyzes the second reaction in the glutaminolytic pathway) in AML. Their results suggest that AML cells preferentially express the GAC isoform of GLS, with much lower expression levels of the KGA isoform. Moreover, they find that AML cases with complex cytogenetics and certain AML molecular subtypes express the highest levels of GAC, suggesting that targeting glutaminolysis in these cases could be an effective therapeutic approach. Consistently, treatment of AML cell lines and AML primary cells with specific GLS inhibitors, such as CB-839 or BPTES, results in decreased cell viability and increased apoptosis. These results further reinforce the importance of glutaminolysis in AML reported by previous studies [2,3]. In addition, 13C and 15 N-isotope labeling experiments demonstrated that inhibition of GLS with CB-839 blocks glutamine utilization and results in decreased levels, and decreased isotope labeling of glutamate, aspartate and several TCA cycle intermediates. Moreover, and in line with a previous report [4], their results suggest that targeting glutaminolysis in AML cases harboring IDH1/IDH2 mutations could be a particularly attractive therapeutic approach. Thus, CB-839 treatment promoted cell growth arrest, reduced the levels of the oncometabolite 2-HG and promoted myeloid differentiation.This study adds up to previous literature that genetically demonstrated the therapeutic benefits of targeting glutaminase in different cancer types. Specifically, germinal loss of one Gls allele resulted in blunted tumor progression in a mouse model of hepatocellular carcinoma (HCC) [5]. Moreover, secondary deletion of both copies of Gls in already established tumors resulted in significant antileukemic effects, and highly sy...

Centrosomes and associated proteins in pathogenesis and treatment of breast cancer

“…Increased expression in CHK1 and WEE1 also appears to facilitate long-term survival of HER2-positive breast tumor cells ( 45 ) through the repair of DNA damage, dysregulation of the cell cycle and the evasion of apoptosis. On the other hand, inhibition of CHK1/WEE1 halts the progression of the cell cycle, causing DNA damage and premature entry of the cell into the M phase, which may trigger selective destruction of cancer cells ( 227 ).…”