Last Updated: 01/03/2024

Development of cancer prevention method using antimalarial drug artesunate and elucidation of its molecular mechanism

Objectives

*The title and abstract were machine translated from Japanese

This research uses a drug (artesunate), which is used worldwide as an antimalarial drug, to investigate the effects on the Wnt signal pathway, the identification of intracellular proteins that directly bind to the drug, and the effectiveness and side effects of the drug in living organisms. 

Principal Institution

National Cancer Center Japan (NCC)

Principal Investigators / Focal Persons

Takahiro Hamoya

Rationale and Abstract

Continuing from last year, the effect of artesunate on intestinal carcinogenesis was investigated using cultured cells and model animals (mice). This year, the true binding protein was first derived from the candidate population of artesunate binding protein analyzed by mass spectrometry last year. As a method, the expression of each candidate protein was knocked down using siRNA, and the effect on TCF / LEF transcription activity (Wnt signal) was evaluated. Furthermore, it was investigated whether the inhibitory effect on TCF / LEF transcription activity disappeared when artesunate was administered while the expression level of each protein was decreased. As a result, the RAN protein was finally identified as an artesunate-binding protein. The RAN protein is known as a cytoplasmic internuclear transport regulator, and mainly regulates the transport of proteins having NLS sequences from the cytoplasm to the nucleus. Next, when the expression level of RAN protein by artesunate administration was examined using the Western blotting method, no effect was observed. Based on this, we considered that artesunate inhibits the function of RAN protein rather than suppressing it, and focused on TCF4 and TCF1 / TCF7, which contain NLS sequences, among the Wnt signaling-related proteins. Then, when the protein expression levels of TCF4 and TCF1 / TCF7 at the time of administration of artesunate were examined, it was confirmed that the expression level of TCF1 / TCF7 was decreased by the administration of artesunate. Furthermore, when the intracellular localization of TCF1 / TCF7 was evaluated using the immunofluorescent staining method, it was confirmed that the intracellular expression level was decreased and the cytoplasmic expression level was increased by the administration of artesunate. These results indicate that artesunate inhibits the nuclear translocation of TCF1 / TCF7 by binding to the RAN protein, and ultimately suppresses Wnt signaling-controlled cell proliferation and intestinal polyp production.

Date

Apr 2019 — Mar 2021

Total Project Funding

$19,451

Funding Details
Japan Society for the Promotion of Science (JSPS)

Grant ID: 19J10184
2,100,000 JPY
Project Site

Japan

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