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Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m⁶A signaling.

ABSTRACT: Purpose: The implementation of targeted therapies for acute myeloid leukemia (AML) has been challenging. Fat mass and obesity associated protein (FTO), an mRNA N⁶-methyladenosine (m⁶A) demethylase, functions as an oncogene that promotes leukemic oncogene-mediated cell transformation and leukemogenesis. Here, we investigated the role of Saikosaponin-d (SsD) in broad anti-proliferation effects in AML and evaluated the m⁶A demethylation activity by targeting FTO of SsD. Methods: It was examined whether and how SsD regulates FTO/m⁶A signaling in AML. The pharmacologic activities and mechanisms of actions of SsD in vitro, in mice, primary patient cells, and tyrosine kinase inhibitors-resistant cells were determined. Results: SsD showed a broadly-suppressed AML cell proliferation and promoted apoptosis and cell-cycle arrest both in vitro and in vivo. Mechanistically, SsD directly targeted FTO, thereby increasing global m⁶A RNA methylation, which in turn decreased the stability of downstream gene transcripts, leading to the suppression of relevant pathways. Importantly, SsD also overcame FTO/m⁶A-mediated leukemia resistance to tyrosine kinase inhibitors. Conclusion: Our findings demonstrated that FTO-dependent m⁶A RNA methylation mediated the anti-leukemic actions of SsD, thereby opening a window to develop SsD as an epitranscriptome-base drug for leukemia therapy.

SUBMITTER: Sun K

PROVIDER: S-EPMC8058711 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m6A signaling.

Sun Kaiju K Du Yangyang Y Hou Yuzhu Y Zhao Mingyue M Li Jiajia J Du Yazhe Y Zhang Lingxiao L Chen Changbao C Yang Hongmei H Yan Fei F Su Rui R

Theranostics 20210331 12

Purpose: The implementation of targeted therapies for acute myeloid leukemia (AML) has been challenging. Fat mass and obesity associated protein (FTO), an mRNA N6-methyladenosine (m6A) demethylase, functions as an oncogene that promotes leukemic oncogene-mediated cell transformation and leukemogenesis. Here, we investigated the role of Saikosaponin-d (SsD) in broad anti-proliferation effects in AML and evaluated the m6A demethylation activity by targeting ...[more]

PMID: 33897884

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Project description:IntroductionOvarian cancer (OC) is known for its high mortality rate. Although sodium citrate has anti-tumor effects in various cancers, its effect and mechanism in OC remain unclear.ObjectivesTo analyze the inhibitory effect of sodium citrate on ovarian cancer cells and the underlying mechanism.MethodsCell apoptosis was examined by TUNEL staining, flow cytometry, and ferroptosis was examined intracellular Fe2+, MDA, LPO assays, respectively. Cell metabolism was examined by OCR and ECAR measurements. Immunoblotting and immunoprecipitation were used to elucidate the mechanism.ResultsThis study suggested that sodium citrate not only promoted ovarian cancer cell apoptosis but also triggeredferroptosis, manifested as elevated levels of Fe2+, LPO, MDA andlipid ROS production. On one hand, sodium citrate treatment led to a decrease of Ca2+ content in the cytosol by chelatingCa2+, which further inhibited the Ca2+/CAMKK2/AKT/mTOR signaling, thereby suppressing HIF1α-dependent glycolysis pathway and inducing cell apoptosis. On the other hand, the chelation of Ca2+ by sodium citrate resulted in inactivation of CAMKK2 and AMPK, leading to increase of NCOA4-mediated ferritinophagy, causing increased intracellular Fe2+ levels. More importantly, the inhibition of Ca2+/CAMKK2/AMPK signaling pathway reduced the activity of the MCU and Ca2+ concentration within the mitochondria, resulting in an increase in mitochondrial ROS. Additionally, metabolomic analysis indicated that sodium citrate treatment significantly increased de novo lipid synthesis. Altogether, these factors contributed to ferroptosis. As expected, Ca2+ supplementation successfully reversed the cell death and decreased tumor growth induced by sodium citrate. Inspiringly, it was found that coadministration of sodium citrate increased the sensitivity of OC cells to chemo-drugs.ConclusionThese results revealed that the sodium citrate exerted its anti-cancer activity by inhibiting Ca2+/CAMKK2-dependent cell apoptosis and ferroptosis. Sodium citrate will hopefully serve as a prospective compound for OC treatment and for improvingthe efficacy of chemo-drugs.

Dataset Information

Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m⁶A signaling.

Publications

Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m<sup>6</sup>A signaling.

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