Details

Autor(en) / Beteiligte

• Chen, Shengmiao
• Wu, Yiran
• Gao, Yang
• Wu, Chenxu
• Wang, Yuetong
• Hou, Chun
• Ren, Miao
• Zhang, Shuyuan
• Zhu, Qi
• Zhang, Jiali
• Yao, Yufeng
• Huang, Mei
• Qi, Yingchuan B.
• Liu, Xue-Song
• Horng, Tiffany
• Wang, Haopeng
• Ye, Dan
• Zhu, Zhengjiang
• Zhao, Suwen
• Fan, Gaofeng

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2023-10, Vol.42 (10), p.113246-113246, Article 113246

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. [Display omitted] •CRISPR-Cas9 screening identifies PTGES3 as an invasion suppressor in ovarian cancer•PTGES3 is associated with the glycolytic rate-limiting enzyme PFKL•PTGES3-mediated prostaglandin E2 production elicits allosteric inhibition of PFKL•Loss of PTGES3 facilitates the epithelial-mesenchymal transition Chen et al. identify a tumor-suppressive gene, PTGES3, and a tumor-suppressive metabolite, PGE2, in ovarian cancer cells, which behave as a “glycolytic rheostat.” They elucidate the mechanism of how PGE2 allosterically inhibits the activity of the glycolytic rate-limiting enzyme PFKL, providing a potential molecular vulnerability for treating ovarian cancer metastasis.