Key Takeaways & Executive Findings
- •• PDK1 is upregulated in epithelial ovarian cancer (EOC) tissues and cell lines, correlating with poor prognosis. • PDK1 promotes EOC cell proliferation, migration, and invasion by upregulating BGN expression and activating the NF-κB pathway. • PDK1 and BGN interact in the cytoplasm, with PDK1 enhancing BGN mRNA stability. • Targeting PDK1/BGN axis may offer novel therapeutic strategies and biomarkers for EOC diagnosis and treatment.
Abstract
Pyruvate dehydrogenase kinase 1 (PDK1) is a new therapeutic target that is dysregulated in multiple tumors. This study aims to explore the potential role and regulatory mechanism of PDK1 in epithelial ovarian cancer (EOC). We detect PDK1 expression in EOC tissues and cells using qRT-PCR and western blot analysis, and the effects of PDK1 on EOC cell malignant behaviors are explored. RNA sequencing analyses are performed to explore the differentially expressed genes in PDK1-silenced EOC cells. Furthermore, tumor-bearing mouse models are established to assess the impacts of PDK1 and BGN on EOC tumor growth and metastasis in vivo. The results show that PDK1 is upregulated in EOC tissues and cell lines. Biglycan (BGN) is downregulated in PDK1-silenced EOC cells, and its expression is positively correlated with PDK1 levels in EOC tissues. PDK1 depletion inhibits EOC cell proliferation, migration and invasion. Mechanistically, PDK1 and BGN are colocalized in the cytoplasm of EOC cells and interact with each other. PDK1 positively regulates BGN expression by enhancing BGN mRNA stability. BGN overexpression partially reverses the anti-tumor effects of PDK1 depletion on EOC cell malignant behaviors. PDK1 has also been revealed to upregulate BGN to activate the NF-κB oncogenic pathway in EOC cells. Additionally, PDK1 accelerates tumor growth and metastasis by modulating BGN expression. In conclusion, PDK1 functions as an oncogene, facilitating EOC progression by upregulating BGN and activating the NF-κB pathway. These findings may provide valuable biomarkers for the diagnosis and treatment of EOC.
1. Introduction
Epithelial ovarian cancer (EOC) is one of the most common malignant tumors of the female reproductive system and severely endangers the life and health of women worldwide [1]. Because of the lack of specific symptoms and early detection methods, EOC patients are often diagnosed with advanced-stage disease [2], but the 5-year survival rate at the late stage is lower than 30% [3]. CA125 and HE4 are valuable diagnostic biomarkers for ovarian cancer, especially for evaluating chemotherapeutic efficacy and clinical outcomes. However, these biomarkers remain insufficiently reliable for screening early-stage ovarian cancer for diagnosis [4,5]. Moreover, the treatment of ovarian cancer is limited by chemoresistance and recurrence, and targeted therapy is suggested to have clinical benefits [6,7]. Hence, understanding the molecular mechanism of EOC and exploring promising diagnostic biomarkers and therapeutic targets for EOC are essential.
The identification of novel therapeutic targets easily modulated by small molecules contributes to targeted therapy in cancer. PDK1 is abnormally expressed in various cancers and is involved in cancer progression. For example, PDK1 silencing suppresses breast cancer cell migration and invasion [8]. PDK1 facilitates hypopharyngeal carcinoma metastasis by inducing epithelial-mesenchymal transition (EMT) via the Notch1 pathway [9]. PDK1 is highly expressed in hepatocellular carcinoma (HCC) and enhances the resistance of HCC cells to radiotherapy by activating PI3K signaling; promoting HCC cell migration, invasion, and EMT; and enhancing cancer cell stemness [10]. PDK1 is upregulated in non-small cell lung cancer (NSCLC) cells, and PDK1 silencing inhibits the survival of NSCLC cells via the Hippo-YAP/IRS2 pathway [11]. Additionally, PDK1 is negatively correlated with CD8+ T-cell infiltration in ovarian cancer, and PDK1 knockdown is linked to improved CD8+ T-cell function and survival in tumor-bearing mice [12]. On the basis of our previous report, the PDK1 gene has significant clinical and prognostic value in the management of EOC. EOC patients with lower PDK1 expression have a higher overall survival rate [13]. This evidence implies that PDK1 may play a critical role in EOC, and the effects and underlying mechanisms of PDK1 targeting are expected to be further explored.
Biglycan (BGN), a constituent of the small leucine-rich proteoglycan family, plays a vital role in modulating cellular adhesion, migration, cell proliferation, autophagy, inflammation, survival, cell morphology, and motility [14‒18]. Previous studies have demonstrated the high expression of BGN in various tumor tissues [19‒21]. Moreover, BGN has been reported to be an oncogene in a variety of cancers, including pancreatic, esophageal, gastric and endometrial cancer [22,23]. In addition, BGN reportedly enhances the ...
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Lei Zhang, Lina Yan, Xin Fu, Ziqi Tao, Shuna Liu, Rong Li, Ting Wang, Yepeng Mao, Wenwen Shang, Mi Gong, Xuemei Jia, Fang Wang (2026). PDK1 promotes epithelial ovarian cancer progression by upregulating BGN. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024186
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Frequently Asked Questions
What is the role of PDK1 in epithelial ovarian cancer?
PDK1 is upregulated in EOC and promotes cancer cell proliferation, migration, and invasion by upregulating BGN and activating the NF-κB pathway, thereby facilitating tumor progression and metastasis.
How does PDK1 regulate BGN expression?
PDK1 positively regulates BGN expression by enhancing BGN mRNA stability, leading to increased BGN protein levels in EOC cells.
What is the clinical significance of the PDK1/BGN axis in EOC?
The PDK1/BGN axis may serve as a potential therapeutic target and provide valuable biomarkers for the diagnosis and treatment of epithelial ovarian cancer.
Does PDK1 affect the NF-κB pathway in EOC?
Yes, PDK1 upregulates BGN to activate the NF-κB oncogenic pathway, which contributes to the malignant behaviors of EOC cells.
What methods were used to study PDK1 and BGN in this research?
The study used qRT-PCR, western blot analysis, RNA sequencing, and tumor-bearing mouse models to assess the expression and effects of PDK1 and BGN on EOC progression.
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