Sulforaphane selectively inhibits glucose metabolism in PIK3CA-mutated ovarian cancer cells

Abstract

Introduction: PIK3CA mutations are prevalent in ovarian cancer (OC) and drive cancer progression by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Sulforaphane (SFN), a natural compound derived from cruciferous vegetables, exhibits antitumor effects; however, its specific mechanisms, especially those related to metabolic reprogramming in PIK3CA-mutated cancers, remain unclear.

Objective: This study investigates the alterations in glucose metabolism and the selective inhibitory effects of SFN in PIK3CA-mutated OC cells.

Methods: Clinical samples from OC patients were analyzed to determine PIK3CA mutation status and its prognostic relevance to patient outcome. PIK3CA-mutated and wild-type OC cell lines were used for in vitro analysis. Glycolysis and mitochondrial respiration were assessed using the Seahorse XF Analyzer. Gene and protein expression were analyzed through RNA sequencing, real-time quantitative polymerase chain reaction, and Western blotting. Metabolite levels were m-easured through untargeted mass spectrometry. The effects of SFN were validated in vitro and in a mouse xenograft model.

Results: PIK3CA mutations were associated with poorer progression-free survival in OC patients. PIK3CA-mutated OC cells exhibited enhanced glycolysis and tricarboxylic acid (TCA) cycle activity compared to wild-type cells. SFN selectively inhibited the proliferation of PIK3CA-mutated cells by suppressing glycolysis and the TCA cycle, downregulating key glycolytic enzymes (e.g., hexokinase 1 and 2) and reducing TCA cycle intermediates (e.g., α-ketoglutaric acid and citrate). Mechanistically, SFN inhibited the PI3K/Akt pathway, resulting in reduced Akt phosphorylation. In vivo, SFN more effectively inhibited tumor growth in mice bearing PIK3CA-mutated xenografts.

Conclusion: PIK3CA mutations enhance both glycolysis and the TCA cycle in OC. SFN selectively inhibits the growth of PIK3CA-mutated OC cells by targeting the PI3K/Akt pathway, leading to the suppression of glucose metabolism. These findings highlight the therapeutic potential of SFN for PIK3CA-mutated OC.

Keywords

PIK3CA mutation / Ovarian cancer / Glucose metabolism

Acknowledgements

The authors thank all patients and their families, as well as the contributors from the First Affiliated Hospital of Zhengzhou University who participated in this study.

Funding

This study was funded by the Natural Science Foundation of Henan (242300421273), the Beijing Science and Technology Innovation Medical Development Foundation (KC2021-JX-0186-130), the CSCO-Zai Ding Cancer Treatment Research Fund project (Y-zai2022/ms-0246), the National Outstanding Youth Science Fund Project of the National Natural Science Foundation of China, (81802770), and the Henan Provincial Health and Health Commission, Joint Co-construction Project of Medical Science and Technology Tackling Program in Henan Province (2018020056).

Conflict of interest

The authors declare no competing interests.

Author contributions

Conceptualization: Linlin Li

Formal analysis: Linlin Li, Ya Xie, Di Chen

Investigation: Zijiao Li, Yinli Su

Methodology: Linlin Li, Ya Xie, Di chen, Zijiao Li

Writing–original draft: Zijiao Li, Yinli Su

Writing–review & editing: Zijiao Li, Yinli Su, Han Wu, Liying Qin, Wan Fu, Xinyu Wang, Xuerou Wang, Longyang Li

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Approval no.: ChiECRCT20210071). All animal experiments were approved by the Animal Care Committee of the First Affiliated Hospital of Zhengzhou University (Approval no.: 2022-KY-0740-003). In addition, all experiments were conducted in accordance with relevant guidelines and regulations.

Consent for publication

Informed consent was obtained from all participants and/or their legal guardians. Participants have given their consent for data publication.

Availability of data

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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