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

doi:10.1016/j.celrep.2023.113246

Allosterically inhibited PFKL via prostaglandin E2 withholds glucose metabolism and ovarian cancer invasiveness

Cell Rep. 2023 Oct 31;42(10):113246. doi: 10.1016/j.celrep.2023.113246. Epub 2023 Oct 12.

Authors

Shengmiao Chen¹, Yiran Wu², Yang Gao³, Chenxu Wu¹, Yuetong Wang¹, Chun Hou¹, Miao Ren¹, Shuyuan Zhang⁴, Qi Zhu¹, Jiali Zhang¹, Yufeng Yao¹, Mei Huang¹, Yingchuan B Qi¹, Xue-Song Liu¹, Tiffany Horng¹, Haopeng Wang¹, Dan Ye⁴, Zhengjiang Zhu⁵, Suwen Zhao⁶, Gaofeng Fan⁷

Affiliations

¹ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
² iHuman Institute, ShanghaiTech University, Shanghai, China.
³ Interdisciplinary Research Center on Biology and Chemistry and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
⁴ 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.
⁵ Interdisciplinary Research Center on Biology and Chemistry and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. Electronic address: jiangzhu@sioc.ac.cn.
⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai, China; iHuman Institute, ShanghaiTech University, Shanghai, China. Electronic address: zhaosw@shanghaitech.edu.cn.
⁷ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: fangf@shanghaitech.edu.cn.

PMID: 37831605
DOI: 10.1016/j.celrep.2023.113246

Abstract

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.

Keywords: CP: Cancer; CP: Metabolism; CRISPR-Cas9 screening; EMT; PFKL; PGE2; PTGES3; TET2; fumarate; invasion; metastasis; ovarian cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation
Dinoprostone*
Female
Glucose / metabolism
Humans
Liver / metabolism
Neoplasm Invasiveness
Ovarian Neoplasms* / pathology
Phosphofructokinase-1 / genetics
Phosphofructokinases

Substances

Dinoprostone
Phosphofructokinases
Phosphofructokinase-1
Glucose