Phenethyl isothiocyanate suppresses the metastasis of ovarian cancer associated with the inhibition of CRM1-mediated nuclear export and mTOR-STAT3 pathway

Abstract

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 IC 50 values of PEITC on SKOV3 and HO8910 cell line were 42.14 mM and 37.29 mM, respectively. PEITC inhibits the migration and invasion of SKOV3 and HO8910 cells in vitro. Oral administration of 10 mmol 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 mTOR S2448 and downstream effectors STAT3 S727 , 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.Abbreviations: CRM1, chromosomal region maintenance 1; DMSO, dimethyl sulfoxide; EOC, epithelial ovarian cancer; IHC, immunohistochemistry; MMP2/9, matrix metalloproteinase 2/9; mTOR, mammalian target of rapamycin; OS, overall survival; PEITC, phenethyl isothiocyanate; STAT3, signal transducers and activators of transcription factors 3

Inhibition of autophagy potentiates the anti‐metastasis effect of phenethyl isothiocyanate through JAK2/STAT3 pathway in lung cancer cells

“…Our previous study showed that PEITC and BITC suppress metastasis potential of lung cancer cells . Interestingly, other groups also revealed the inhibitory effect of isothiocyanates on metastasis in ovarian cancer, prostate cancer, breast cancer, and cervical carcinoma . Although these studies indicated that several mechanisms are involved, such as the inhibition of CRM1‐mediated nuclear export and mTOR‐STAT3 pathway, regulation on miRNA‐194, and involvement of HIF‐1alpha, however, the role of autophagy has not been elucidated.…”

PIM Kinases and Their Relevance to the PI3K/AKT/mTOR Pathway in the Regulation of Ovarian Cancer

“…mTOR over-activation can cause OC and it is also related to ovarian diseases such as polycystic ovarian syndrome [ 67 ]. The mTOR is caught up in OC metastasis and its inhibition causes suppression of OC metastasis [ 68 ]. CCL18, a chemotactic cytokine, causes cancer and thought to be a biomarker for epithelial OC.…”

Inhibition of chromosomal region maintenance 1 suppresses the migration and invasion of glioma cells via inactivation of the STAT3/MMP2 signaling pathway

“…Previous reports have suggested that STAT3 is persistently activated through constant nucleocytoplasmic shuttling, which is regulated by CRM1 [48,49]. STAT3 contains several NES elements through which it binds to CRM1 for nuclear export [49,50]. Inhibition of CRM1-mediated nuclear export can slow down the nucleocytoplasmic shuttling of activated STAT3 resulting in reduced tyrosine phosphorylation, decreased induction of STAT3 target genes, and increased apoptosis [51].…”