Allosterically inhibited PFKL via prostaglandin E2 withholds glucose metabolism and ovarian cancer invasiveness
Shengmiao Chen,
Yiran Wu,
Yang Gao,
Chenxu Wu,
Yuetong Wang,
Chun Hou,
Miao Ren,
Shuyuan Zhang,
Qi Zhu,
Jiali Zhang,
Yufeng Yao,
Mei Huang,
Yingchuan B. Qi,
Xue-Song Liu,
Tiffany Horng,
Haopeng Wang,
Dan Ye,
Zhengjiang Zhu,
Suwen Zhao,
Gaofeng Fan
Affiliations
Shengmiao Chen
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Yiran Wu
iHuman Institute, ShanghaiTech University, Shanghai, China
Yang Gao
Interdisciplinary Research Center on Biology and Chemistry and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Chenxu Wu
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Yuetong Wang
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Chun Hou
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Miao Ren
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Shuyuan Zhang
Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, and Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
Qi Zhu
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Jiali Zhang
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Yufeng Yao
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Mei Huang
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Yingchuan B. Qi
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Xue-Song Liu
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Tiffany Horng
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Haopeng Wang
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Dan Ye
Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, and Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
Zhengjiang Zhu
Interdisciplinary Research Center on Biology and Chemistry and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; Corresponding author
Suwen Zhao
School of Life Science and Technology, ShanghaiTech University, Shanghai, China; iHuman Institute, ShanghaiTech University, Shanghai, China; Corresponding author
Gaofeng Fan
School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Corresponding author
Summary: Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.
