南开大学丁亚辉等研究人员合作发现，BE-43547A2通过靶向eEF1A1并破坏其与FoxO1的相互作用在低氧条件下对人类胰腺癌细胞产生选择性抑制作用。相关论文于2025年1月21日在线发表在《中国药理学报》杂志上。

研究人员探讨了BE-43547A2在人体胰腺癌细胞中的低氧选择性分子机制。研究人员发现，BE-43547A2在五种胰腺癌细胞（PANC-1、Capan-2、MIA PaCa-2、AsPC-1和PaTu8988T）中表现出低氧选择性的细胞毒性，其在低氧条件下的IC50值显著低于常氧条件下的值。研究人员证明，BE-43547A2在低氧条件下直接与PaTu8988T细胞中的eEF1A1蛋白结合。

此外，研究人员揭示，低氧显著升高了HIF1α、FoxO1和eEF1A1在五种胰腺癌细胞中的表达水平。eEF1A1与FoxO1在细胞质中相互作用，而BE-43547A2破坏了这一相互作用，导致FoxO1的核转位，并最终抑制了低氧条件下的JAK/STAT3信号通路。

这项研究表明，BE-43547A2通过靶向eEF1A1，破坏其与FoxO1的相互作用，从而在低氧条件下抑制人类胰腺癌细胞的功能。该化合物可作为潜在的低氧选择性治疗方法。

研究人员表示，低氧是肿瘤微环境的一个关键特征，导致许多化疗失败并诱导更具侵袭性和耐药性的癌症表型。目前，能够靶向低氧的化合物和治疗方法非常少。来自链霉菌（Streptomyces sp.）的BE-43547A2是针对PANC-1、MCF-7和K562细胞系的最具低氧选择性的化合物之一。

附：英文原文

Title: BE-43547A2 exerts hypoxia-selective inhibition on human pancreatic cancer cells through targeting eEF1A1 and disrupting its association with FoxO1

Author: Liu, Can, Liu, Can, Liu, Guang-ju, Wang, Meng-meng, Jiao, Yan, Sun, Yuan-jun, Guo, Hui, Wang, Liang, Lu, Ya-xin, Chen, Yue, Ding, Ya-hui

Issue&Volume: 2025-01-21

Abstract: Hypoxia is a key feature of the tumor microenvironment that leads to the failure of many chemotherapies and induces more aggressive and resistant cancer phenotypes. Up to date, there are very few compounds and treatments that can target hypoxia. BE-43547A2 from Streptomyces sp. was one of the most hypoxia-selective compounds against PANC-1, MCF-7, and K562 cell lines. In this study, we investigated the molecular mechanism underlying the hypoxia selectivity of BE-43547A2 in human pancreatic cancer cells. We showed that BE-43547A2 displayed hypoxia-selective cytotoxicity in five pancreatic cancer cells (PANC-1, Capan-2, MIA PaCa-2, AsPC-1, and PaTu8988T) with IC50 values under hypoxia considerably lower than those under normoxia. We demonstrated that BE-43547A2 is directly bound to eEF1A1 protein in PaTu8988T cells under hypoxia. Furthermore, we revealed that hypoxia significantly elevated the expression levels of HIF1α, FoxO1, and eEF1A1 in the five pancreatic cancer cells; eEF1A1 interacted with FoxO1 in the cytoplasm, which was disrupted by BE-43547A2 followed by the nuclear translocation of FoxO1 and ultimate inhibition of JAK/STAT3 signaling pathway under hypoxia. This study reveals that BE-43547A2, targeting eEF1A1, disrupts its interaction with FoxO1 in human pancreatic cancer cells under hypoxia. This compound could serve as a potential hypoxia-selective therapy.

DOI: 10.1038/s41401-024-01461-y

Source: https://www.nature.com/articles/s41401-024-01461-y