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Penfluridol targets septin7 to suppress endometrial cancer by septin7-Orai/IP3R-Ca 2+ -PIK3CA pathway

Published:19 December 2024 DOI: 10.1016/j.isci.2024.111640 PMID: 39850355
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

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.

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