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Open AccessArticle

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

by Soo Hyun Lim 1,†, Ki Hong Nam 1,†, Kyungtae Kim 1,†, Sang Ah Yi 1, Jaecheol Lee 1,2,3 and Jeung-Whan Han 1,*
1
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea
2
Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Korea
3
Imnewrun Biosciences Inc., Suwon 16419, Korea
*
Author to whom correspondence should be addressed.
Authors contributed equally.
Pharmaceuticals 2020, 13(10), 302; https://doi.org/10.3390/ph13100302
Received: 11 September 2020 / Revised: 29 September 2020 / Accepted: 8 October 2020 / Published: 12 October 2020
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. View Full-Text
Keywords: rosmarinic acid methyl ester; ovarian cancer; FOXM1; migration; invasion; cisplatin resistance rosmarinic acid methyl ester; ovarian cancer; FOXM1; migration; invasion; cisplatin resistance
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    Link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158604
    Description: Table S1. The list of 242 down-regulated genes in RAME treated SKOV-3 ovarian cancer cells (|log2 (Fold change)| > 1, p-value < 0.05). Figure S1. FOXM1 expression level in ovarian cancer patients. The relative mRNA expression of FOXM1 in TCGA cohort (Normal : 8, Cancer: 586) and two Oncomine dataset: Welsh Ovarian (Normal : 4, Cancer: 28) and Benome Ovarian (Normal : 10, Cancer: 185) Figure S2. Apoptotis marker gene expression by RAME treatment in ovarian cancer cell. (A) The relative mRNA expression of apoptosis marker genes in SKOV-3 cells by RAME treatment (40μM). (B) The relative mRNA expression of apoptosis marker genes in TOV-21G cells by RAME treatment (40μM). Error bars represent the mean ± SEM (n = 3). ns : not significant. Figure S3. The mRNA level of FOXM1 in SKOV-3 and TOV-21G cells. The relative mRNA expression of FOXM1 in SKOV-3 and TOV-21G ovarian cancer cell lines. Error bars represent the mean ± SEM (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001; unpaired t test.
MDPI and ACS Style

Lim, S.H.; Nam, K.H.; Kim, K.; Yi, S.A.; Lee, J.; Han, J.-W. Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1. Pharmaceuticals 2020, 13, 302.

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