Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

作者全名："Gao, Lixia; Yang, Fan; Tang, Dianyong; Xu, Zhigang; Tang, Yan; Yang, Donglin; Sun, Deping; Chen, Zhongzhu; Teng, Yong"

作者地址："[Gao, Lixia; Tang, Dianyong; Xu, Zhigang; Tang, Yan; Yang, Donglin; Chen, Zhongzhu] Chongqing Univ Arts & Sci, Coll Pharm, Natl & Local Joint Engn Res Ctr Targeted & Innovat, Chongqing Key Lab Kinase Modulators Innovat Med, Chongqing 402160, Peoples R China; [Gao, Lixia; Tang, Dianyong; Xu, Zhigang; Tang, Yan; Yang, Donglin; Chen, Zhongzhu] Chongqing Univ Arts & Sci, Int Acad Targeted Therapeut & Innovat, Chongqing 402160, Peoples R China; [Gao, Lixia] Chongqing Acad Chinese Mat Med, Chongqing 400065, Peoples R China; [Yang, Fan; Teng, Yong] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Sch Med, 201 Dowman Dr, Atlanta, GA 30322 USA; [Sun, Deping] Chongqing Med Univ, Univ Town Hosp Chongqing Med Univ, Chongqing 401331, Peoples R China"

通信作者："Teng, Y (通讯作者)，Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Sch Med, 201 Dowman Dr, Atlanta, GA 30322 USA."

来源：JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000906377600002

JCR分区：Q1

影响因子：11.3

年份：2023

卷号：42

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：ENO2; PKM2; HNSCC; Glucose metabolism; Cell cycle; AP-III-a4

摘要："Background: 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. Methods: 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. Results: 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. Conclusion: Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC."

基金机构：National Natural Science Foundation of China; Natural Science Founda-tion Project of Chongqing [82203593]; Science and Technology Research Program of Chongqing Municipal Education Commission [cstc2021jcyj-bsh0239]; Winship Invest$ Team Science Award [KJQN202101326]

基金资助正文："This work was supported by the grant funded by the National Natural Science Foundation of China 82203593 (to LG), the Natural Science Founda-tion Project of Chongqing cstc2021jcyj-bsh0239 (to LG), the Science and Technology Research Program of Chongqing Municipal Education Commission KJQN202101326 (to LG). This work was also supported in part by Winship Invest$ Team Science Award (to YT )."