Targeting Glutamine Metabolism through Glutaminase Inhibition Suppresses Cell Proliferation and Progression in Nasopharyngeal Carcinoma

Author(s):

Chang Su*, Minghan Li, Yuxin Yang, Ziying Wang, Qianru Wang, Weijia Wang, Xuemin Ma, Rongrong Jie, Huaihong Chen*, Xiangping Li* and Juan Lu*   Pages 1944 - 1957 ( 14 )

Abstract:

<p> Background: Glutaminase (GLS), the key enzyme involved in glutamine metabolism, has been identified as a critical player in tumor growth and progression. The GLS inhibitor CB-839 has entered several clinical trials against a variety of tumors. </p> <p> Objective: Our study aimed to investigate the role and underlying mechanism of GLS and its inhibitor CB-839 in nasopharyngeal carcinoma (NPC). </p> <p> Methods: The expression, downstream genes, and signaling pathways of GLS in NPC were determined by real-time polymerase chain reaction (RT-PCR), PCR array, western blotting (WB), and immunohistochemical staining (IHC), and the phenotype of GLS was confirmed by <i>in vivo</i> experiments of subcutaneous tumor formation in mice and <i>in vitro</i> experiments of functional biology, including Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, transwell migration, and Boyden invasion assay. Finally, it was also verified whether the treatment of NPC cells by GLS inhibitor CB-839 can change various biological functions and protein expression to achieve the purpose of blocking tumor progression. </p> <p> Results: GLS was remarkably overexpressed in NPC cells and tissues, predicting a poor overall survival of NPC patients. GLS promoted cell cycle, proliferation, colony formation, migratory, and invasive capacities by regulating Cyclin D2 (CCND2) <i>via</i> PI3K/AKT/mTOR pathway in NPC <i>in vitro</i> and <i>in vivo</i>. Notably, CB-839 showed an effective anti-NPC tumor effect by blocking the biological functions of the tumor. </p> <p> Conclusion: The first innovative proof is that GLS promotes cell proliferation by regulating CCND2 via PI3K/AKT/mTOR pathway in NPC, and GLS inhibitor CB-839 may serve as a new potential therapeutic target for NPC treatment.</p>

Keywords:

GLS, proliferation, CCND2, PI3K/AKT/mTOR pathway, nasopharyngeal carcinoma, CB-839.

Affiliation:

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