Butorphanol Inhibits the Malignant Biological Behaviors of Ovarian Cancer Cells via Down-Regulating the Expression of TMEFF1

PURPOSE: An important issue with compounds for treating ovarian cancer is the development of drug resistance and side effects. Butorphanol is a synthetic opioid. Opioids have been shown to promote or prevent tumor growth and metastasis. This research aimed to reveal the affection of Butorphanol on the malignant biological behaviors of ovarian cancer cells. METHODS: Different concentrations of Butorphanol were used to treat ovarian cancer cell lines, ES-2 and SKOV3. Biological functions of cells were performed by CCK-8 assay, colony formation assay, apoptosis analysis, transwell assays and scratch assays. The differences in the transcriptome of the Butorphanol treated and negative control (NC) cells were analyzed by RNA-Seq. RESULTS: Butorphanol treatment significantly inhibited the viability, colony-forming, migration and invasion of ES-2 and SKOV3 cells compared to NC. Furthermore, Butorphanol treatment obviously induced the apoptosis of ES-2 and SKOV3 cells and regulated the expression of apoptosis-related proteins. Additionally, Butorphanol treatment significantly reduced the expression of p-AKT, p-mTOR and P70S6K without affecting the expression of AKT and mTOR in ES-2 and SKOV3 cells. Forty-four genes were identified to up-regulate its expression, while 17 genes were identified to down-regulate its expression in Butorphanol-treated cells. Among them, TMEFF1 was found to be significantly down-regulated in Butorphanol-treated cells. Additionally, the restoration of TMEFF1 expression complemented the inhibitory effect of Butorphanol treatment on cell proliferation and invasion. CONCLUSION: In conclusion, Butorphanol is a compound with potential to treat ovarian cancer. TMEFF1 may play a key role in inhibiting the malignant proliferation and metastasis of Butorphanol treatment on ovarian cancer cells.