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Targeting Echinococcus multilocularis Stem Cells by Inhibition of the Polo-Like Kinase EmPlk1

Abstract : Background: Alveolar echinococcosis (AE) is a life-threatening disease caused by larvae of the fox-tapewormEchinococcusmultilocularis. Crucial to AE pathology is continuous infiltrative growth of the parasite’s metacestode stage, which is drivenby a population of somatic stem cells, called germinative cells. Current anti-AE chemotherapy using benzimidazoles isineffective in eliminating the germinative cell population, thus leading to remission of parasite growth upon therapydiscontinuation. Methodology/Principal findings: We herein describe the characterization of EmPlk1, encoded by the geneemplk1, whichdisplays significant homologies to members of the Plk1 sub-family of Polo-like kinases that regulate mitosis in eukaryoticcells. We demonstrate germinative cell-specific expression ofemplk1by RT-PCR, transcriptomics, andin situhybridization.We also show that EmPlk1 can induce germinal vesicle breakdown when heterologously expressed inXenopusoocytes,indicating that it is an active kinase. This activity was significantly suppressed in presence of BI 2536, a Plk1 inhibitor that hasbeen tested in clinical trials against cancer. Addition of BI 2536 at concentrations as low as 20 nM significantly blocked theformation of metacestode vesicles from cultivatedEchinococcusgerminative cells. Furthermore, low concentrations of BI2536 eliminated the germinative cell population from mature metacestode vesiclesin vitro, yielding parasite tissue that wasno longer capable of proliferation. Conclusions/Significance: We conclude that BI 2536 effectively inactivatesE. multilocularisgerminative cells in parasitelarvaein vitroby direct inhibition of EmPlk1, thus inducing mitotic arrest and germinative cell killing. Since germinative cellsare decisive for parasite proliferation and metastasis formation within the host, BI 2536 and related compounds are verypromising compounds to complement benzimidazoles in AE chemotherapy
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https://hal.univ-lille.fr/hal-03200299
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Soumis le : vendredi 16 avril 2021 - 13:57:19
Dernière modification le : mardi 19 octobre 2021 - 23:56:32
Archivage à long terme le : : samedi 17 juillet 2021 - 18:41:59

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Andreas Schubert, Uriel Koziol, Katia Cailliau-Maggio, Mathieu Vanderstraete, Colette Dissous, et al.. Targeting Echinococcus multilocularis Stem Cells by Inhibition of the Polo-Like Kinase EmPlk1. PLoS Neglected Tropical Diseases, Public Library of Science, 2014, PLoS neglected tropical diseases, 8 (6), pp.e2870. ⟨10.1371/journal.pntd.0002870⟩. ⟨hal-03200299⟩

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