NDLI: AU-1 from Agavaceae plants causes transient increase in p21/Cip1 expression in renal adenocarcinoma ACHN cells in an miR-34-dependent manner

Content Provider	Springer Nature Link
Author	Fuji, Tomofumi Yokosuka, Akihito Higurashi, Hideaki Yokokawa, Rina Sakurai, Ryo Harashima, Wataru Miki, Yuichi Fujiwara, Yasuyuki Mimaki, Yoshihiro Hayakawa, Makio
Copyright Year	2016
Abstract	Here, we show that AU-1, spirostanol saponin isolated from Agavaceae plants, causes a transient increase in cyclin-dependent kinase inhibitor (CDKI) p21/Cip1 through the upregulation of miRNAs, miR-34 and miR-21. AU-1 stimulated p21/Cip1 expression without exerting cytotoxicity against different types of carcinoma cell lines. In renal adenocarcinoma ACHN cells, AU-1 transiently elevated the expression level of p21/Cip1 protein without marked increases in p21/Cip1 mRNA levels. Rapid and transient increases in miR-34 and miR-21, both of which are known to upregulate p21/Cip1, were observed in AU-1-treated cells. Inhibitor for miR-34 and for miR-21 significantly blocked the AU-1-caused increase in p21/Cip1, indicating that elevation of p21/Cip1 protein by AU-1 is dependent on these microRNAs. We further clarified that NAD-dependent deacetylase SIRT1, a direct target of miR-34, is decreased by the treatment with AU-1. Furthermore, we found that SIRT1-knockdown increases p21/Cip1 protein levels in an miR-21-dependent manner. On the other hand, ectopic expression of p21/Cip1 resulted in the lowered expression of miR-34 and miR-21, suggesting that reciprocal regulation exists between p21/Cip1 and these miRNAs. We propose that the following feedback network composed of miR-34/SIRT1/miR-21/p21 is triggered by the treatment with AU-1: in cells treated with AU-1, transient elevation of miR-34 leads to the downregulation of SIRT1, thereby miR-21 is freed from SIRT1-dependent suppression. Then, elevated miR-21 upregulates p21/Cip1 protein, followed by the suppression of miR-34 expression.
Starting Page	36
Ending Page	43
Page Count	8
File Format	PDF
ISSN	13403443
Journal	Journal of Natural Medicines
Volume Number	71
Issue Number	1
e-ISSN	18610293
Language	English
Publisher	Springer Japan
Publisher Date	2016-07-07
Publisher Place	Tokyo
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Agave utahensis p21/Cip1 miR-34 miR-21 SIRT1 Pharmacology/Toxicology Plant Sciences Complementary & Alternative Medicine Medicinal Chemistry Pharmacy
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Drug Discovery Molecular Medicine Complementary and Alternative Medicine Pharmaceutical Science

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