Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development.
Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development.
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DOI：
10.1186/s13046-022-02574-0
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发表时间：
2023-01-02
期刊：
影响因子：
--
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中科院分区：
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--
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烯醇化酶2（Enolase 2，ENO 2）是肿瘤代谢过程中的关键糖酵解酶，在与糖酵解无关的多种细胞过程中发挥着多种功能。相对于正常组织，ENO 2在头颈部鳞状细胞癌（HNSCC）组织中高度表达;然而，其在HNSCC恶性肿瘤中的影响和潜在的调控机制仍不清楚。通过生物信息学、qRT-PCR、蛋白质印迹、免疫荧光、免疫组织化学、免疫沉淀和ChIP-PCR测定来检查分子改变。通过细胞内ATP和葡萄糖水平评估代谢变化。采用动物实验评价ENO抑制剂的治疗效果。ENO 2是HNSCC细胞增殖和糖酵解所必需的，令人惊讶的是，这部分是通过控制PKM 2蛋白稳定性及其核转位来实现的。从机制上讲，ENO 2表达的缺失通过泛素-蛋白酶体途径促进PKM 2蛋白降解，并通过灭活AKT信号传导阻止细胞质PKM 2向细胞核的转换，导致PKM 2介导的糖酵解通量和CCND 1相关细胞周期进程的阻断。此外，用ENO抑制剂AP-III-a4治疗在临床前小鼠模型中显著诱导HNSCC缓解。我们的工作阐明了ENO 2依赖性HNSCC发展的信号基础，为建立一种新的ENO 2靶向治疗HNSCC提供了证据。在线版本包含补充材料，可通过10.1186/s13046-022-02574-0获得。
Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a “moonlighting” protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear. Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor. ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model. Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC. The online version contains supplementary material available at 10.1186/s13046-022-02574-0.
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烯醇酶抑制剂，用于靶向ENO1删除的癌症。
影响因子：
20.8
作者：
Lin YH;Satani N;Hammoudi N;Yan VC;Barekatain Y;Khadka S;Ackroyd JJ;Georgiou DK;Pham CD;Arthur K;Maxwell D;Peng Z;Leonard PG;Czako B;Pisaneschi F;Mandal P;Sun Y;Zielinski R;Pando SC;Wang X;Tran T;Xu Q;Wu Q;Jiang Y;Kang Z;Asara JM;Priebe W;Bornmann W;Marszalek JR;DePinho RA;Muller FL
通讯作者：
Muller FL
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
DOI：
10.1016/j.omto.2021.12.026
发表时间：
2022-03-17
期刊：
Molecular therapy oncolytics
影响因子：
--
作者：
Huang CK;Sun Y;Lv L;Ping Y
通讯作者：
Ping Y
影响因子：
10.3
作者：
Lalonde, Chloe S.;Teng, Yong;Saba, Nabil F.
通讯作者：
Saba, Nabil F.
影响因子：
37.3
作者：
Hsu MC;Hung WC
通讯作者：
Hung WC