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Research Articles: Therapeutics, Targets, and Development

Luteolin sensitizes the anticancer effect of cisplatin via c-Jun NH₂-terminal kinase–mediated p53 phosphorylation and stabilization

¹ Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; ² School of Medicine, Zhejiang University, Zhejiang, Hangzhou, People's Republic of China; and ³ Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore

Requests for reprints: Han-Ming Shen, Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597. Phone: 65-6516-4998; Fax: 65-6779-1489. E-mail: cofshm{at}nus.edu.sg

Abstract

Luteolin is an important flavonoid with a potential anticancer effect. In this study, we examined the molecular mechanisms involved in the sensitization effect of luteolin on cancer cell killing induced by cisplatin, an important cancer chemotherapeutic agent. First, we provided evidence that the sensitization effect of luteolin on cisplatin-induced apoptosis is p53 dependent, as such effect is only found in p53 wild-type cancer cells but not in p53 mutant cancer cells. Moreover, knockdown of p53 by small interfering RNA made p53 wild-type cancer cells resistant to luteolin and cisplatin. Second, we observed a significant increase of p53 protein level in luteolin-treated cancer cells without increase of p53 mRNA level, indicating the possible effect of luteolin on p53 posttranscriptional regulation. Third, we identified the critical role of c-Jun NH₂-terminal kinase (JNK) in regulation of p53 protein stability: luteolin activates JNK, and JNK then stabilizes p53 via phosphorylation, leading to reduced ubiquitination and proteasomal degradation. Finally, by using an in vivo nude mice xenograft model, we confirmed that luteolin enhanced the cancer therapeutic activity of cisplatin via p53 stabilization and accumulation. In summary, data from this study reveal a novel molecular mechanism involved in the anticancer effect of luteolin and support its potential clinical application as a chemosensitizer in cancer therapy. [Mol Cancer Ther 2007;6(4):1338–47]

Grant support: Singapore National Medical Research Council grant 0949/2005, National University of Singapore academic research fund (H.M. Shen), National University of Singapore research scholarship (R.X. Shi), and Centre for Environmental Health Research, National University of Singapore (Q. Huang).

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.

Note: R. Shi and Q. Huang contributed equally to this work.

⁴ R. Shi and H.M. Shen, unpublished data.

Received 10/16/06; revised 2/ 2/07; accepted 2/23/07.