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J. Biol. Chem., Vol. 283, Issue 30, 20664-20673, July 25, 2008

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Cocoa Procyanidins Suppress Transformation by Inhibiting Mitogen-activated Protein Kinase Kinase^*

Nam Joo Kang¹, Ki Won Lee^¶1, Dong Eun Lee, Evgeny A. Rogozin, Ann M. Bode, Hyong Joo Lee², and Zigang Dong³

From the Hormel Institute, University of Minnesota, Austin, Minnesota 55912, Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-742, Republic of Korea, and ^¶Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea

Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit neoplastic cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 µg/ml and 40 µM, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-B induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 µM) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-B, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and neoplastic cell transformation.

Received for publication, January 10, 2008 , and in revised form, May 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA120388, CA111536, CA88961, and CA81064. This work was also supported by the Hormel Foundation and by grants from the BioGreen21 Program (20070301-034-042), Rural Development Administration, the Korea Science and Engineering Foundation (R01-2007-000-11957-0), and the Ministry of Science and Technology, Republic of Korea. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 82-2-880-4860; Fax: 82-2873-5095; E-mail: leehyjo{at}snu.ac.kr. ³ To whom correspondence may be addressed: Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912. Tel.: 507-437-9600; Fax: 507-437-9606; E-mail: zgdong{at}hi.umn.edu.

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