Penfluridol targets septin7 to suppress endometrial cancer by septin7-Orai/IP3R-Ca2+-PIK3CA pathway
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 <i>in vitro</i> and <i>in vivo</i>. 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-Ca<sup>2+</sup>-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.
Authors
- Fei Mao (ORCID: https://orcid.org/0000-0001-5871-6878)
- Jinlian Wei (ORCID: https://orcid.org/0000-0002-2628-342X)
- Beibei Liu (ORCID: https://orcid.org/0000-0003-4880-3075)
- Xianwu Ling (ORCID: https://orcid.org/0000-0002-0096-3793)
- Xiao Sun (ORCID: https://orcid.org/0000-0002-1150-5755)
- Yudong Wang (ORCID: https://orcid.org/0000-0002-4708-6345)
- Jian Li (ORCID: https://orcid.org/0000-0002-7521-8798)
- Lijuan Li (ORCID: https://orcid.org/0000-0002-2507-5856)
- Xiaokang Li (ORCID: https://orcid.org/0000-0001-8154-551X)
- Liu Xiao-hu (ORCID: https://orcid.org/0000-0001-8821-3120)
- Hui‐Wen Wu (ORCID: https://orcid.org/0000-0001-7226-2251)
- Wei Ni
- Lingyi Song
Institutions
- Shihezi University (CN)
- East China University of Science and Technology (CN)
- Shanghai Jiao Tong University (CN)
- Hainan University (CN)
- International Peace Maternity & Child Health Hospital (CN)
Publication Details
- Journal
- iScience
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1016/j.isci.2024.111640
- Citations
- 3
- Primary Topic
- Endometriosis Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Innovative Research Group Project of the National Natural Science Foundation of China
- National Natural Science Foundation of China
- State Key Laboratory of Bioreactor Engineering
- Program of Shanghai Academic Research Leader