Next Generation Sequencing Facilitates Analysis of Penfluridol Treatment and Control SamplesTranscriptomes
Endometrial cancer (EC) is the most common cancer of the female reproductive tract and one of the few cancers for which survival has not substantially improved since the mid-1970s, reflecting few advances in treatment. The main therapeutic method of EC is surgical therapy assisted with radiotherapy and chemotherapy at present. Progesterone is the first-line drug for conservative treatment, but it faces the challenge of drug resistance and is ineffective for type II EC. There is an urgent clinical need to find new therapeutic targets and candidate drugs. Repurposing of existing drugs is a good strategy to discover new candidate drugs. Herein, 33 antipsychotics in our drug library were screened and penfluridol (PFD) was found to exhibit excelent anti-EC activity. Then the molecular target of PFD was revealed as the GTP-binding protein Septin7 using activity-based protein profiling (ABPP) techniques. Septin7 functioned as a tumor suppressor in EC and PFD exhibited weaker anticancer properties in Septin7 knockdown EC cells, indicating that Septin7 is essential for PFD biological activity. Notably, our investigations of PFD mechanism suggested that PFD binding with Septin7 inhibited the interaction of Septin7 with microtubules, thereby inhibiting microtubule polymerization and arresting the cell cycle in G1 phase. In addition, RNA-seq analysis and western blot showed that PFD could induce cell apoptosis by regulating Septin7-PIK3CA-AKT-Caspase3 pathway. Finally, PFD displayed significant in vivo antitumor efficacy in KLE endometrial cancer xenograft models without causing obvious side effects. Taken together, our findings revealed new target and mechanistic insights in EC therapeutic strategy and offer a potential candidate for the treatment of EC, especially progesterone resistance EC. Overall design: Examination of Penfluridol treatment and control samples in ISK cells by RNA-seq, in triplicate.