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

Acta Pharmacologica Sinica volume 46, pages 1433–1444 (2025)Cite this article

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.

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Fig. 1: BE-43547A2 targeted eEF1A1 in hypoxia to exerts its hypoxia selectivity.
Fig. 2: eEF1A1 correlated with the hypoxia-selective growth inhibitory effect of BE-43547A2.
Fig. 3: BE-43547A2 regulated JAK/STAT3 pathway in hypoxia by targeting eEF1A1.
Fig. 4: Hypoxia promoted the expression of HIF1α, FoxO1, and eEF1A1 proteins.
Fig. 5: eEF1A1 interacted with FoxO1 to regulate JAK/STAT3 signaling pathway.
Fig. 6: BE-43547A2 disrupted the interaction of eEF1A1 and FoxO1 in hypoxia.
Fig. 7: BE-43547A2 derivative effectively suppressed tumor growth in xenografts.

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Acknowledgements

We acknowledge the support of the National Natural Science Foundation of China (No. 82273794, No. 81903456 to YHD), Guangzhou Laboratory (GZNL2023A01002), and the Natural Science Foundation of Tianjin (No. 20JCQNJC02080 to YHD).

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Authors and Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China

    Can Liu  (刘璨), Can Liu  (刘灿), Guang-ju Liu, Yan Jiao, Yuan-jun Sun, Hui Guo, Liang Wang, Ya-xin Lu, Yue Chen & Ya-hui Ding

  2. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300350, China

    Can Liu  (刘璨), Yue Chen & Ya-hui Ding

  3. College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China

    Can Liu  (刘璨)

  4. Accendatech Co., Ltd., Tianjin, China

    Meng-meng Wang

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  1. Can Liu  (刘璨)
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Contributions

CL (刘璨) performed most of the cellular, biochemical protein purification, and animal experiments. LW conducted the synthesis of BE-43547A2 probe and NMP-BE-43547A2 citrate. GJL and YJS synthesized BE-43547A2 probe and NMP-BE-43547A2 citrate. CL (刘灿), MMW, and YJ contributed to the cellular and animal experiments. HG and YXL contributed to protein purification and animal experiments. YHD and YC initiated the project, led the project team, designed the experiment plans, analyzed the results. CL (刘璨) , YC, and YHD wrote the manuscript.

Corresponding authors

Correspondence to Yue Chen or Ya-hui Ding.

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Competing interests

Meng-meng Wang was an employee of Accendatech Co., Ltd and had no commercial interests.

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Liu, C., Liu, C., Liu, Gj. et al. BE-43547A2 exerts hypoxia-selective inhibition on human pancreatic cancer cells through targeting eEF1A1 and disrupting its association with FoxO1. Acta Pharmacol Sin 46, 1433–1444 (2025). https://doi.org/10.1038/s41401-024-01461-y

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