Penfluridol targets septin7 to suppress endometrial cancer by septin7-Orai/IP3R-Ca2+-PIK3CA pathway

Lingyi Song; Huiwen Wu; Xiao Sun; Xiaohu Liu; Xianwu Ling; Wei Ni; Lijuan Li; Beibei Liu; Jinlian Wei; Xiaokang Li; Jian Li; Yudong Wang; Fei Mao

doi:10.1016/j.isci.2024.111640

Penfluridol targets septin7 to suppress endometrial cancer by septin7-Orai/IP3R-Ca²⁺-PIK3CA pathway

iScience. 2024 Dec 19;28(1):111640. doi: 10.1016/j.isci.2024.111640. eCollection 2025 Jan 17.

Authors

Lingyi Song¹, Huiwen Wu¹, Xiao Sun², Xiaohu Liu¹, Xianwu Ling¹, Wei Ni¹, Lijuan Li², Beibei Liu¹, Jinlian Wei¹, Xiaokang Li¹, Jian Li^{1

3

4}, Yudong Wang^{2

5}, Fei Mao¹

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
³ Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China.
⁴ Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, China.
⁵ Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai 200030, China.

Abstract

Phenotypic screening of existing drugs is a good strategy to discover new drugs. Herein, 33 psychotherapeutic drugs in our drug library were screened by phenotypic screening and penfluridol (PFD) was found to exhibit excellent anti-endometrial cancer (EC) activity both in vitro and in vivo. Furthermore, the molecular target of PFD was identified as septin7, a tumor suppressor in EC. In septin7-deficient EC cells and xenograft mouse models, PFD exhibited weaker anti-cancer properties, indicating that septin7 was essential for the tumor inhibitory activity. Notably, PFD could induce cell apoptosis by regulating the septin7-Orai/IP3R-Ca²⁺-PIK3CA pathway. In addition, PFD attenuates the interaction of septin7-tubulin, thereby inhibiting microtubule polymerization. In summary, this study revealed a target and mechanistic insights into EC therapeutic strategies and identified a potential candidate agent for the treatment of EC.

Keywords: Cancer; Cell biology; Functional aspects of cell biology.