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Research Articles: Therapeutics, Targets, and Development

A bioactive withanolide Tubocapsanolide A inhibits proliferation of human lung cancer cells via repressing Skp2 expression

¹ Graduate Institute of Medicine, College of Medicine and ² Graduate Institute of Natural Products, Kaohsiung Medical University; ³ Institute of Biomedical Sciences, National Sun Yat-Sen University; and ⁴ National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, Taiwan, Republic of China

Requests for reprints: Hui-Chiu Chang, Shih-Chuan 1st Road, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China. Fax: 886-7-3903991; E-mail: m740127{at}kmu.edu.tw and Yang-Chang Wu, Shih-Chuan 1st Road, Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China. Fax: 886-7-3114773; E-mail: yachwu{at}kmu.edu.tw

Abstract

Withanolides are generally defined as C₂₈ steroidal lactones built on an intact or rearranged ergostane skeleton and have been shown to exhibit antiproliferative activity on various types of cancer cells. In this study, we investigated the effect of a new withanolide Tubocapsanolide A isolated from Tubocapsicum anomalum and addressed its molecular action. Tubocapsanolide A inhibited proliferation of A549, H358, and H226 human lung cancer cells via induction of G₁ growth arrest. We found that Tubocapsanolide A treatment led to up-regulation of cyclin E, p21, and p27, whereas other cyclins and cyclin-dependent kinases were not affected in A549 cells. Conversely, Skp2, the F-box protein that is implicated in the mediation of degradation of p21 and p27, was significantly down-regulated. Chromatin immunoprecipitation assay suggested that Tubocapsanolide A suppressed Skp2 expression by inhibiting the binding of Rel A to the nuclear factor-B site of Skp2 gene promoter. In addition, we showed that inhibition of Skp2 is a critical step for the suppression of cell proliferation by Tubocapsanolide A because ectoexpression of Skp2 effectively reversed Tubocapsanolide A–induced p27 up-regulation and growth inhibition in human lung cancer cells. Collectively, we have identified Skp2 as a molecular target for Tubocapsanolide A and suggest that this withanolide may be useful for the prevention or treatment of cancer cells with Skp2 overexpression. [Mol Cancer Ther 2007;6(5):1572–8]

Grant support: Kaohsiung Medical University Research Foundation (Q096012) and the National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center (H-C. Chang).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/31/06; revised 3/ 2/07; accepted 3/27/07.