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.

• Authors: Kaiju Sun, Yangyang Du, Yuzhu Hou, Mingyue Zhao, Jiajia Li, Yazhe Du, Lingxiao Zhang, Changbao Chen, Hongmei Yang, Fei Yan, Rui Su
• Journal: Theranostics (Theranostics) Vol. 11 Issue 12 Pg. 5831-5846 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33897884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Protein Kinase Inhibitors
• RNA, Messenger
• Saponins
• Oleanolic Acid
• N-methyladenosine
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• FTO protein, human
• Protein-Tyrosine Kinases
• Adenosine
• saikosaponin D

Topics

• Adenosine (analogs & derivatives, metabolism)
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO (metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• HL-60 Cells
• Humans
• K562 Cells
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Methylation (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (metabolism)
• RNA, Messenger (genetics)
• Saponins (pharmacology)
• Signal Transduction (drug effects)
• U937 Cells