Enterolactone combined with m6A Reader IGF2BP3 inhibits malignant angiogenesis and disease progression in ovarian cancer

Mengzhi Xu; Yi Guo; Fengge Wang; Caiji Lin; Danli Cao; Yu Yan; Shuhui Chai; Yufan Zhao; Shimenghui Deng; Jiayu Wei; Xin Kang; Yuhan Liu; Yinuo Zhang; Lingjie Luo; Shu-Lin Liu; Huidi Liu

doi:10.1016/j.phymed.2024.156343

Enterolactone combined with m6A Reader IGF2BP3 inhibits malignant angiogenesis and disease progression in ovarian cancer

Phytomedicine. 2024 Dec 21:136:156343. doi: 10.1016/j.phymed.2024.156343. Online ahead of print.

Authors

Mengzhi Xu¹, Yi Guo¹, Fengge Wang², Caiji Lin³, Danli Cao¹, Yu Yan¹, Shuhui Chai¹, Yufan Zhao¹, Shimenghui Deng¹, Jiayu Wei¹, Xin Kang¹, Yuhan Liu¹, Yinuo Zhang¹, Lingjie Luo¹, Shu-Lin Liu⁴, Huidi Liu⁵

Affiliations

¹ Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China.
² College of Life Science, Northeast Forestry University, Harbin, Heilongjiang, 150040, PR China.
³ Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China; The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, China.
⁴ Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, T2N 4N1, Canada. Electronic address: slliu@hrbmu.edu.cn.
⁵ Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, T2N 4N1, Canada. Electronic address: hdliu@hrbmu.edu.cn.

PMID: 39765033
DOI: 10.1016/j.phymed.2024.156343

Abstract

Background: Among all gynecological cancers, ovarian cancer is the leading cause of death. Epithelial ovarian cancer (EOC) accounts for over 85 % of ovarian cancer cases and is characterized by insidious onset, early metastasis, and a high recurrence rate. Alterations in gut microbiota, often as a consequence of chemotherapy, can promote cancer development and exacerbate the disease. The m6A reader IGF2BP3 is a regulator in the occurrence and progression of various tumors and is associated with angiogenesis. Enterolactone (ENL) has demonstrated significant anti-tumor activity against various human cancers, including EOC. However, whether ENL could interact with IGF2BP3 to suppress EOC remains unclear.

Purpose: This study aims to investigate suppressive effects of ENL upon combining with IGF2BP3 on EOC and elucidates the underlying mechanism.

Methods: The Cell Counting Kit-8 and crystal violet assays were used to assess tumor cell proliferation. Scratch and Transwell assays were employed to evaluate tumor cell migration, while tube formation assays were utilized to examine angiogenesis. Western blotting was used to measure the expression levels of IGF2BP3, VEGF, PI3K, AKT1, p-PI3K, and p-AKT1. An in vivo xenograft nude mouse model was established, fecal samples were collected, and 16S rDNA sequencing was performed to analyze gut microbiota in association with the suppressive effects of ENL and its interactions with IGF2BP3.

Results: IGF2BP3 is highly expressed in EOC and is positively correlated with poor survival in EOC patients. ENL reduces IGF2BP3 expression in EOC, thereby inhibiting the IGF2BP3-mediated VEGF/PI3K/AKT signaling pathway and suppressing the proliferation, migration, invasion, and angiogenesis of EOC. Additionally, ENL ameliorates gut microbiome, especially in conjunction with shIGF2BP3.

Conclusion: ENL interacts with IGF2BP3 and suppresses its expression in EOC, leading to the deactivation of the IGF2BP3-mediated VEGF/PI3K/AKT signaling pathway and the subsequent inhibition of angiogenesis. The combination of ENL and shIGF2BP3 demonstrates a synergistic effect on EOC. ENL also ameliorates the gut microbiome, especially in conjunction with shIGF2BP3, to suppress EOC.

Keywords: Angiogenesis; Enterolactone; IGF2BP3; Ovarian cancer; VEGF.