Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1

Abstract

Rosmarinic acid methyl ester (RAME), a derivative of rosmarinic acid (RA), is reported to have several therapeutic effects, including anti-tumor effects against cervical cancer. However, its anti-tumor effects in ovarian cancer is unclear. In this study, we studied the molecular pathways associated with the anti-tumor effects of RAME in ovarian cancer. To identify the effects of RAME in ovarian cancer, RNA sequencing was performed in RAME-treated ovarian cancer cells; we found that RAME treatment downregulated the genes closely involved with the target genes of the transcription factor Forkhead box M1 (FOXM1). It was reported that FOXM1 is overexpressed in a variety of cancer cells and is associated with cell proliferation and tumorigenesis. Therefore, we hypothesized that FOXM1 is a key target of RAME; this could result in its anti-tumor effects. Treatment of ovarian cancer cells with RAME-inhibited cell migration and invasion, as shown by wound healing and transwell migration assays. To examine whether RAME represses the action of FOXM1, we performed quantitative RT-PCR and ChIP-qPCR. Treatment of ovarian cancer cells with RAME decreased the mRNA expression of FOXM1 target genes and the binding of FOXM1 to its target genes. Moreover, FOXM1 expression was increased in cisplatin-resistant ovarian cancer cells, and combination treatment with RAME and cisplatin sensitized the cisplatin-resistant ovarian cancer cells, which was likely due to FOXM1 inhibition. Our research suggests that RAME is a promising option in treating ovarian cancer patients, as it revealed a novel molecular pathway underlying its anti-tumor effects.

New 1,1-diarylethylene FOXM1 inhibitors potently reduce intracellular FOXM1 and suppress high-grade serous ovarian carcinoma cell viability

“…We were limited in our comparison of the NB compounds to the most widely used and accessible reported FOXM1 inhibitors. Although many natural compounds have been shown to inhibit FOXM1 [53][54][55] , their anti-cancer effects may not be due to inhibition of FOXM1 given their likely pleiotropic nature. Other FOXM1 inhibitors, such as 7-di uoromethoxyl-5,4'-di-n-octyl-genistein (which was synthesized from the natural compound genistein) 56 , are not currently commercially available.…”

A Comprehensive Review of Rosmarinic Acid: From Phytochemistry to Pharmacology and Its New Insight

“…Due to the C8′-carboxyl group, RA can combine with some alcohol compounds to obtain some esters in the plants such as rosmarinic acid methyl ester, ethyl ester, n -propyl ester, and n -butyl ester. These alkyl rosmarinates have demonstrated anti-oxidative, anti-inflammatory, anti-allergic, anti-bacterial, anti-cardiovascular disease, and other activities [ 198 , 199 , 200 , 201 , 202 , 203 ]. In addition, 3- O -methyl rosmarinic acid, 3- O -caffeoyl rosmarinic acid, 3′- O -methyl rosmarinic acid, 4′- O -methyl rosmarinic acid (shimobashiric acid B), and 3, 3′- O -diethyl rosmarinic acid are the natural products of RA substituted by a methyl, ethyl, and even caffeoyl groups on the C3-, C3′-, and C4′-hydroxyl groups.…”

FOXM1 Inhibition in Ovarian Cancer Tissue Cultures Affects Individual Treatment Susceptibility Ex Vivo

“…Nevertheless, tumor response, seen in apoptosis and proliferation rate, is detected after monotherapy as well as the combination. Unexpected ways of response could be explained by the fact that FOXM1 regulates various downstream target genes and BRCA2 is also affected by different regulators [ 26 , 31 ], suggesting other involved pathways which are currently under investigation in cell culture studies [ 54 , 55 ]. Thiostrepton further is a potent proteasome inhibitor and inhibits the degradation of pro-apoptotic factors, indicating another cause of apoptotic effects on tumor cells [ 56 , 57 ].…”