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

IF 2.9 4区生物学 Q3 CELL BIOLOGY Journal of Molecular Histology Pub Date : 2025-01-09 DOI:10.1007/s10735-024-10342-x

Shidong Chen, Cuixia Zhang, Honglang Huang, Yuhuan Wang, Mingjian Lian, Guolin Hong

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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.

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PDK1激活WNT4/ β-catenin/FOXO1通路促进宫颈癌转移和EMT过程

目的探讨低氧条件下丙酮酸脱氢酶激酶1 （PDK1）对宫颈癌细胞增殖、迁移和上皮间质转化（EMT）的影响，探讨PDK1在宫颈癌（CC）中的作用。方法采用慢病毒shRNA技术建立spdk1沉默的CC细胞株。细胞迁移和侵袭分别通过划痕和Transwell试验进行评估。细胞活性和凋亡相关蛋白表达水平采用MTT和western blotting检测。转录组测序阐明了受PDK1沉默影响的调控途径，救援实验证实了其潜在机制。采用裸鼠异种移植模型验证PDK1沉默对CC进展的影响。结果spdk1沉默可减少低氧条件下的迁移、侵袭和细胞活性，同时促进细胞凋亡。转录组学分析显示，PDK1抑制下调了WNT4/β-catenin/FOXO1通路，降低了emt相关蛋白的表达。机制上，PDK1通过akt介导的GSK3β失活，抑制β-catenin的磷酸化，促进EMT和抗凋亡基因转录，从而增强β-catenin的稳定性。结论靶向PDK1可能通过调节WNT4/β-catenin/FOXO1通路及其相关的EMT和凋亡过程，为CC提供新的治疗策略。

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来源期刊

Journal of Molecular Histology 生物-细胞生物学

CiteScore

5.90

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： The Journal of Molecular Histology publishes results of original research on the localization and expression of molecules in animal cells, tissues and organs. Coverage includes studies describing novel cellular or ultrastructural distributions of molecules which provide insight into biochemical or physiological function, development, histologic structure and disease processes. Major research themes of particular interest include: - Cell-Cell and Cell-Matrix Interactions; - Connective Tissues; - Development and Disease; - Neuroscience. Please note that the Journal of Molecular Histology does not consider manuscripts dealing with the application of immunological or other probes on non-standard laboratory animal models unless the results are clearly of significant and general biological importance. The Journal of Molecular Histology publishes full-length original research papers, review articles, short communications and letters to the editors. All manuscripts are typically reviewed by two independent referees. The Journal of Molecular Histology is a continuation of The Histochemical Journal.