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Research Articles: Therapeutics, Targets, and Development

Methyl-3-indolylacetate inhibits cancer cell invasion by targeting the MEK1/2-ERK1/2 signaling pathway

¹ Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore and ² Center for Disease Control and Prevention of Guang Dong, Guangzhou, Guang Dong Province, People's Republic of China

Requests for reprints: Choon-Nam Ong, Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore. Phone: 65-6516-4982; Fax: 65-6779-1489. E-mail: cofongcn{at}nus.edu.sg

Abstract

Epidemiologic studies have suggested an inverse correlation between dietary intake of cruciferous vegetables and cancer risk. It is thus of interest to investigate the anticancer potential of phytochemicals presented in cruciferous vegetables. In this study, methyl-3-indolylacetate (MIA), a cruciferous indole for which the bioactivity has not been previously reported, was found to significantly suppress the invasion of cancer cells stimulated by the 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Our data show that MIA pretreatments inhibited matrix metalloproteinase 9 (MMP-9) expression in a concentration-dependent manner, resulting in decreased MMP-9 activity. By using real-time reverse transcription-PCR, luciferase reporter gene assay, and electrophoretic mobility shift assay, we provided convincing evidence that MIA suppresses MMP-9 gene transcription via targeting the activator protein-1 signaling but not the nuclear factor-B pathway. The TPA-induced mitogen-activated protein kinase (MAPK) activation cascade was also analyzed. Despite extensive activation of major MAPKs [c-Jun NH₂-terminal kinase, p38, and extracellular signal-regulated kinase-1/2 (ERK1/2)] under TPA stimulation, only the ERK1/2 activation and its consequent nuclear translocation were found to be diminished by MIA. Interestingly, MIA did not affect the TPA-induced phosphorylation of either c-Raf or MAPK/ERK kinase-1/2 (MEK1/2), two upstream kinases of ERK. Moreover, using the in vitro kinase assay, MIA was shown to inhibit the kinase activity of MEK1/2, the upstream kinases of ERK, suggesting that MEK is the major molecular target of MIA. In conclusion, data from this study provided new insight into the anticancer potential of MIA, a cruciferous vegetable–derived indole compound. [Mol Cancer Ther 2006;5(12):3285–93]

Grant support: NIH-NCCAM grant R21-AT1945 and the National University of Singapore Centre for Environmental and Occupational Health.

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: S. Zhang and Z. Li contributed equally to this work.

³ Lai et al., data to be published.

⁴ Supplementary material for this article is available at Molecular Therapeutics Online (http://mct.aacrjournals.org/).

Received 5/ 2/06; revised 9/11/06; accepted 10/20/06.