Abstract
PurposeGlutamine (Gln) is essential for the proliferation of most cancer cells, making it an appealing target for cancer therapy. However, the role of Gln in gastric cancer (GC) metabolism is unknown and Gln-targeted therapy against GC remains scarce. The aim of this study was to investigate the relevance of Gln in GC growth and targeting.MethodsExpression of Gln transporter ASCT2 and glutamine synthetase (GS) in the parental and molecularly engineered GC cells or in human GC specimens was determined by RT-PCR and western blot analysis or immunohistochemistry. Cell proliferation and survival was assessed by CCK-8 assay and colony formation assay. Intracellular Gln content was measured by a HPLC system. Effects of ASCT2 and/or GS inhibitor on tumor growth were investigated in xenograft models.ResultsA significant heterogeneity of GC cells was observed with respect to their response to the treatment of ASCT2 inhibitor benzylserine (BenSer). Gln deprivation did not affect the BenSer-resistant cell growth due to endogenous GS expression, whose inhibition remarkably reduced cell proliferation. The differential in vitro sensitivity correlated with overall intracellular Gln content. Combined therapy with both ASCT2 and GS inhibitors produced a greater therapeutic efficacy than the treatment of either inhibitor alone. Furthermore, 77% human GC tissues were found to express moderate and high levels of ASCT2, 12% of which also co-expressed relatively high levels of GS.ConclusionGln mediates GC growth and the therapeutic efficacy of Gln-targeted treatment relies on distinct ASCT2 and GS expression pattern in specific gastric cancer groups.
Highlights
Cancer cells have long been known to experience great metabolism alterations
Since Gln is a versatile nutrient required for the survival and growth of a potentially large subset of tumors, we sought to determine whether its deprivation could differentially affect the growth of the BenSer-sensitive and -resistant gastric cancer (GC) cells
BenSer-sensitive cells were losing their proliferative and reproductive capacities upon Gln deprivation. These data indicated a differential reliance on exogenous Gln among the GC cells, whereby it appeared that only BenSer-sensitive cells required ASCT2-mediated glutamine uptake for cell growth and survival
Summary
Cancer cells have long been known to experience great metabolism alterations. Unlike normal cells which rely on mitochondrial oxidative phosphorylation, most cancer cells instead use aerobic glycolysis for ATP generation even in the presence of abundant oxygen supply, a phenomenon known as “the Warburg effect” (Warburg 1956). The catabolism of Gln is mediated by two different subtypes of mitochondrial glutaminase (kidney or liver-type encoded by GLS or GLS2, respectively) to become glutamate (Glu), a versatile metabolic intermediate that connects with many distinct biological processes such as oncogenic signaling events (Curthoys and Watford 1995; Gao et al 2009; Wang et al 2010). In this regard, targeting glutaminase by a small molecule inhibitor has been demonstrated to inhibit oncogenic transformation (Wang et al 2010). While a positive correlation of GS activity with cell survival and proliferation has been observed in some types of cancers (Kung et al 2011; Tardito et al 2015; Yang et al 2016), few studies have focused on GS as a potential target for Gln-based cancer therapy
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