Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid 28040, Spain; Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid 28040, Spain.
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy.
Neoplasia. 2024 Dec;58:101076. doi: 10.1016/j.neo.2024.101076. Epub 2024 Oct 30.
Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.
糖酵解代谢产生能量和中间产物，用于生物量的产生。与正常组织相比，肿瘤相关的糖酵解在受到肿瘤细胞自主或非自主刺激时会被上调。这种上调的后果有两个方面。首先，糖酵解的代谢效应变得比氧化代谢介导的效应更为重要。其次，糖酵解途径中过度表达的成分（即酶或代谢物）获得了与其代谢效应无关的新功能，这些功能被称为“月光蛋白”功能。这些功能包括诱导突变和其他肿瘤起始事件、对癌症干细胞的影响、诱导癌蛋白表达和/或活性增加、表观遗传和转录修饰、绕过衰老并诱导增殖、促进 DNA 损伤修复和预防 DNA 损伤、抗凋亡作用、抑制药物流入或增加药物流出。上调的代谢功能和获得新的非代谢功能导致支持肿瘤发生的生物学效应：促进肿瘤起始、刺激肿瘤细胞增殖和原发性肿瘤生长、诱导上皮-间充质转化、自噬和转移、免疫抑制作用、诱导耐药和对肿瘤辅助细胞的影响。这些效应对肿瘤患者的预后产生负面影响。基于这些原因，肿瘤相关糖酵解成为抗肿瘤药物发现的一个有吸引力的靶点并不奇怪。然而，到目前为止，糖酵解抑制剂的临床效果并没有达到预期。在这篇综述中，我们提出了一些方法，这些方法可能有助于克服迄今为止在使用糖酵解抑制剂进行治疗时遇到的一些困难。
