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. 2025 Jan 9;56(1):68.
doi: 10.1007/s10735-024-10342-x.

Activation of the WNT4/ β-catenin/FOXO1 pathway by PDK1 promotes cervical cancer metastasis and EMT process

Shidong Chen #  1 , Cuixia Zhang #  2 , Honglang Huang  3 , Yuhuan Wang  2 , Mingjian Lian  1 , Guolin Hong  4
Affiliations

Activation of the WNT4/ β-catenin/FOXO1 pathway by PDK1 promotes cervical cancer metastasis and EMT process

Shidong Chen et al. J Mol Histol. .

Abstract

Objective: This study aimed to elucidate the role of pyruvate dehydrogenase kinase-1 (PDK1) in cervical cancer (CC) by investigating its impact on cell proliferation, migration, and epithelial-mesenchymal transition (EMT) under hypoxic conditions.

Methods: PDK1-silenced CC cell lines were established using lentiviral shRNA technology. Cell migration and invasion were assessed through scratch and Transwell assays, respectively. Cellular activity and apoptosis-related protein expression levels were evaluated using MTT assays and western blotting. Transcriptome sequencing elucidates the regulatory pathways impacted by PDK1 silencing, and rescue experiments confirmed the underlying mechanisms. Xenograft models with nude mice were used to validate the effects of PDK1 silencing on CC progression.

Results: PDK1 silencing reduced migration, invasion, and cellular activity under hypoxic conditions while promoting apoptosis. Transcriptomic analysis revealed that PDK1 suppression downregulated the WNT4/β-catenin/FOXO1 pathway, decreasing EMT-related protein expression. Mechanistically, PDK1 enhanced β-catenin stability by inhibiting its phosphorylation through AKT-mediated GSK3β inactivation, promoting EMT and anti-apoptotic gene transcription.

Conclusions: Targeting PDK1 may provide novel therapeutic strategies specifically for CC by modulating the WNT4/β-catenin/FOXO1 pathway and associated EMT and apoptotic processes.

Keywords: Apoptosis; Cervical cancer; Epithelial-mesenchymal transition; PDK1; WNT4/β-catenin/FOXO1.

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Conflict of interest statement

Declarations. Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests. Conflict of interest: The authors declare no competing interests.

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