Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer

Nam, Ki Hong; Yi, Sang Ah; Nam, Gibeom; Noh, Jae Sung; Park, Jong Woo; Lee, Min Gyu; Park, Jee Hun; Oh, Hwamok; Lee, Jieun; Lee, Kang Ro; Park, Hyun-Ju; Lee, Jaecheol; Han, Jeung‐Whan

doi:10.1186/s12885-019-5997-2

Cited by 25 publications

(26 citation statements)

References 60 publications

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“…Here, we report that beetroot and leaf extracts did not activate the Akt feedback loop even though they efficiently inhibited the mTOR pathway. Nam et al (2019) demonstrated that inhibition of S6K1 in cervical cancer cells enhanced the PARP1 cleavage as reported here with the treatment with leaf and root extract. In accordance with our findings, the inhibition of S6K1 in TE8 esophageal cancer cells also led to the downregulation of cyclin D (S.-H. Kim, Jang, Chau, Pyo, & Um, 2013).…”

Section: Discussionsupporting

confidence: 81%

Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa)

Romero

Pavan

Morelli

et al. 2021

Phytotherapy Research

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Cervical cancer is the fourth leading cause of cancer mortality in women worldwide.Beetroot (Beta vulgaris L.) has bioactive compounds that can inhibit the progression of different types of cancer. To analyze the antiproliferative effects of beet leaf and root extracts, we performed MTT, clonogenic survival, cell cycle analysis, Annexin/PI labeling, and western blotting. Here, we report that 10 and 100 μg/ml of root and leaf extracts decreased cell viability and potentiated rapamycin and cisplatin effects while decreased the number of large colonies, especially at 10 μg/ml (293.6 of control vs. 200.0 of leaf extract, p = .0059; 138.6 of root extract, p = .0002). After 48 hr, 100 μg/ml of both extracts led to increased sub-G1 and G0/G1 populations. In accordance, 100 μg/ml of root extract induced early apoptosis (mean = 0.64 control vs. 1.56 root; p = .048) and decreased cell size (p < .0001). Both extracts decreased phosphorylation and expression of mechanistic Target of Rapamycin (mTOR) signaling, especially by inhibiting ribosomal protein S6 (S6) phosphorylation, increasing cleaved poly(ADP-ribose) polysomerase 1 (PARP1) and Bcl-2-like protein 11 (BIM), and decreasing cyclin D1 expression, which regulates cell cycle progression. Here, we demonstrate that beetroot and leaf extracts could be an efficient strategy against cervical cancer.

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Section: Discussionsupporting

confidence: 81%

Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa)

Romero

Pavan

Morelli

et al. 2021

Phytotherapy Research

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“…Previously, it was reported that RAME induced the autophagy and apoptosis of cervical cancer cells [ 20 ]. To further elucidate the molecular pathways demonstrating its anti-tumor effects against ovarian cancer, we performed the RNA-sequencing of RAME-treated SKOV-3 ovarian cancer cells.…”

Section: Resultsmentioning

confidence: 99%

“…To further elucidate the molecular pathways demonstrating its anti-tumor effects against ovarian cancer, we performed the RNA-sequencing of RAME-treated SKOV-3 ovarian cancer cells. Since 40 µM of RAME treatment showed apoptotic effects in cervical cancer cells [ 20 ], we treated another ovarian cancer cell line, SKOV-3, with 40 µM of RAME. As shown by the RNA-sequencing data, 2789 differentially expressed genes (DEGs) were identified, including 1337 upregulated genes and 1452 downregulated genes ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…RAME also exhibits anti-oxidant and anti-melanogenesis in vivo [ 19 ]. Recently, the anti-cancer effect of RAME via the inhibition of mTOR-S6K1 signaling in cervical cancer was reported [ 20 ]. It was also reported that RAME induced the apoptosis of cervical cancer cells and enhanced the anti-tumor effect of cisplatin in cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…4C). Rapamycin analogs ("rapalogs") are in clinical use against human cancer and act in part by inhibiting S6K (Ferrari, et al 1993, Meng andZheng 2015), and S6K inhibitors are under development as cancer therapeutics (Nam, et al 2019, Pearce, et al 2010, consistent with a wellestablished role of S6K activation in the molecular pathogenesis of multiple cancers.…”

Section: Efficacy Of Ta/dda Mono-and Combination Anti-cancer Therapymentioning

confidence: 99%

Repurposing Tranexamic Acid as an Anticancer Agent

Law

Davis²,

Ghilardi³

et al. 2021

Preprint

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Tranexamic Acid (TA) is a clinically used antifibrinolytic that acts as a lysine mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic lysine and arginine, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

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Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer

Cited by 25 publications

References 60 publications

Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa)

Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa)

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

Repurposing Tranexamic Acid as an Anticancer Agent

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