Wan Shu, Teng Hua, Xiaoyan Xin, Jun Zhang, Jing Lin, Rui Shi, Rong Zhao, Wei Zhang, Ke-Jun Dong, Hongbo Wang, Xing Zhou
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引用次数: 0
摘要
子宫内膜癌(EC)是一种常见的恶性肿瘤,与糖尿病和肥胖等代谢性疾病密切相关。高级糖化终产物(AGEs)是还原糖与生物大分子的氨基反应形成的复杂聚合物,是许多慢性代谢性疾病发生和发展的介质。最新研究表明,AGEs 的积累会影响肿瘤微环境、新陈代谢和信号通路,从而影响肿瘤的恶性进展。然而,AGEs对EC的影响机制尚不清楚。我们的研究旨在探讨AGEs如何通过代谢途径促进EC的发展,并探索其潜在的内在机制。我们的实验结果表明,AGEs通过高级糖化终产物受体(RAGE)上调了胆碱激酶α(CHKA)介导的胆碱代谢,激活了PI3K/AKT通路,增强了EC细胞的恶性生物学行为。虚拟筛选和分子动力学模拟显示,替莫皂苷 A3(timo A3)可以靶向 CHKA,抑制 AGE 诱导的心肌梗死进展,新发现的 CHKA 抑制剂可能成为治疗心肌梗死的新型靶向抑制剂。这项研究提供了新的治疗策略,有助于EC的治疗。
Advanced glycation end products promote the progression of endometrial cancer via activating the RAGE/CHKA/PI3K/AKT signaling pathway.
Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of reducing sugars with the amino groups of biomacromolecules, mediating the occurrence and development of many chronic metabolic diseases. Recent research has demonstrated that the accumulation of AGEs can affect the tumor microenvironment, metabolism, and signaling pathways, thereby affecting the malignant progression of tumors. However, the mechanism by which AGEs affect EC is unclear. Our research aimed to investigate how AGEs promote the development of EC through metabolic pathways and to explore their potential underlying mechanisms. Our experimental results demonstrated that AGEs upregulated the choline metabolism mediated by choline kinase alpha (CHKA) through the receptor for advanced glycation end products (RAGE), activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin A3 (timo A3) could target CHKA to inhibit AGE-induced progression of EC and that a newly discovered CHKA inhibitor could be a novel targeted inhibitor for the treatment of EC. This study provides new therapeutic strategies and contributes to the treatment of EC.
期刊介绍:
Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).