<br>晚期糖基化终末产物通过激活 RAGE/CHKA/PI3K/AKT 信号通路促进子宫内膜癌的进展。,Carcinogenesis

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晚期糖基化终末产物通过激活 RAGE/CHKA/PI3K/AKT 信号通路促进子宫内膜癌的进展。
Carcinogenesis ( IF 3.3 ) Pub Date : 2025-01-20 , DOI: 10.1093/carcin/bgae059
Wan Shu ₁ , Teng Hua ₁ , Xiaoyan Xin ₁ , Jun Zhang ₁ , Jing Lin ₁ , Rui Shi ₁ , Rong Zhao ₁ , Wei Zhang ₁ , Ke-Jun Dong ₁ , Hongbo Wang _{1,

2} , Xing Zhou ₁

Affiliation

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紊乱密切相关。晚期糖基化终产物（AGEs）是由还原糖与生物大分子的氨基反应形成的复杂聚合物，介导许多慢性代谢性疾病的发生和发展。近年来研究表明，AGEs 的积累会影响肿瘤微环境、代谢和信号通路，从而影响肿瘤的恶性进展。然而，AGEs 影响 EC 的机制尚不清楚。本研究旨在探讨 AGEs 如何通过代谢途径促进 EC 的发展，并探讨其潜在的潜在机制。我们的实验结果表明，AGEs 通过晚期糖基化终末产物受体上调胆碱激酶 α （CHKA）介导的胆碱代谢，激活 PI3K/AKT 通路并增强 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，噻沙波宁 A3 可以靶向 CHKA 抑制 AGE 诱导的 EC 进展，并且新发现的 CHKA 抑制剂可能是一种治疗 EC 的新型靶向抑制剂。本研究提供了新的治疗策略，有助于 EC 的治疗。

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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, activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin 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.

更新日期：2024-08-24

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