Phenethyl isothiocyanate suppresses the metastasis of ovarian cancer associated with the inhibition of CRM1-mediated nuclear export and mTOR-STAT3 pathway.
Epithelial ovarian cancer is prone to metastasizing at an early stage, but their mechanisms remain unclear. CRM1 is an important nuclear exportin and inhibitors targeting CRM1 has been explored as an anti-cancer strategy. In previous study, we observed that PEITC could combine with the hydrophobic pocket of CRM1. In this study, we focused on the effects of PEITC on EOC and its mechanisms. Results showed that IC50 values of PEITC on SKOV3 and HO8910 cell line were 42.14 μM and 37.29 μM, respectively. PEITC inhibits the migration and invasion of SKOV3 and HO8910 cells in vitro. Oral administration of 10 μmol PEITC suppressed the metastasis of EOC in a xenograft mouse model in vivo. PEITC treatment decreased the expressions of CRM1 and mTOR (cargo protein of CRM1) in EOC cell lines and in xenograft mouse tissues. Moreover, CRM1-mediated nuclear export was attenuated by PEITC, mTOR accumulated in nucleus, expressions of mTORS2448 and downstream effectors STAT3S727, MMP2 and MMP9 were decreased in a dose- and time-dependent manner. Furthermore, immunohistochemical analysis showed that CRM1 and mTOR were increased in EOC tissues compared with benign ovarian tumors, and related with advanced stage, type II EOC, positive peritoneal cytology and decreased overall survival. In addition, CRM1 was positively correlated with mTOR levels. In conclusion, our data demonstrated that PEITC suppresses the metastasis of EOC through inhibiting CRM1-mediated nuclear export, subsequently suppressing the mTOR-STAT3 pathway. Both CRM1 and mTOR were increased in EOC patients, providing a rationale for further clinical investigation of PEITC in EOC treatment.
['Shao|Wen Yu|WY|', 'Yang|Yong Liang|YL|', 'Yan|Huan|H|', 'Huang|Qian|Q|', 'Liu|Kai Jiang|KJ|', 'Zhang|Shu|S|']
D021581:Active Transport, Cell Nucleus D000818:Animals D016588:Anticarcinogenic Agents D045744:Cell Line, Tumor D005260:Female D006801:Humans D017879:Isothiocyanates D028884:Karyopherins D051379:Mice D008875:Middle Aged D009362:Neoplasm Metastasis D010051:Ovarian Neoplasms D018160:Receptors, Cytoplasmic and Nuclear D050796:STAT3 Transcription Factor D058570:TOR Serine-Threonine Kinases
metastasis ovarian cancer nuclear export CRM1 PEITC mTOR STAT3