Targeting phosphoglycerate kinases by tatridin A, a natural sesquiterpenoid endowed with anti-cancer activity, using a proteomic platform

Frontiers in Molecular Biosciences

Molecular Biosciences

Matteo Mozzicafreddo¹  Federica Pollastro²  Maria Chiara Monti³  Alessandra Tosco³  Antonia Voli⁴  Giusy Ferraro⁴ 

[1] Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Ancona, Italy;Department of Pharmaceutical Sciences, Università Del Piemonte Orientale, Novara, Italy;PlantaChem Srls, Novara, Italy;Department of Pharmacy, Università di Salerno, Fisciano, Italy;Department of Pharmacy, Università di Salerno, Fisciano, Italy;PhD Program in Drug Discovery and Development, Department of Pharmacy, Università di Salerno, Fisciano, Italy;

关键词: sesquiterpenes;    functional proteomics;    PGK1;    CXCR4;    gastric cancer;    cancer dissemination;   

DOI  :  10.3389/fmolb.2023.1212541

 received in 2023-04-26, accepted in 2023-07-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

Tatridin A (TatA) is a germacrane sesquiterpenoid containing one E-double bond and one Z-double bond in its 10-membered ring, which is fused to a 3-methylene-dihydrofuran-2-one moiety. Tatridin A bioactivity has been poorly investigated despite its interesting chemical structure. Here, a functional proteomic platform was adapted to disclose its most reliable targets in leukemia monocytic cells, and phosphoglycerate kinases were recognized as the most affine enzymes. Through a combination of limited proteolysis and molecular docking, it has been discovered that tatridin A interacts with the active domains of phosphoglycerate kinase 1, altering its hinge region, and it can be accountable for tatridin A inhibition potency on enzyme activity. A more detailed tatridin A biological profile showed that it is also fully active against gastric cancer cells, downregulating the mRNA levels of chemokine receptor 4 and β-catenin and inhibiting the invasiveness of living KATO III cells as a direct consequence of phosphoglycerate kinase 1 antagonism.

【 授权许可】

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Copyright © 2023 Ferraro, Voli, Mozzicafreddo, Pollastro, Tosco and Monti.