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J. Biol. Chem., Vol. 283, Issue 8, 5023-5033, February 22, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/8/5023    most recent M705877200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liang, F.-P. Articles by Fu, S.-L. Search for Related Content PubMed PubMed Citation Articles by Liang, F.-P. Articles by Fu, S.-L. Social Bookmarking                      What's this?

Suppression of v-Src Transformation by Andrographolide via Degradation of the v-Src Protein and Attenuation of the Erk Signaling Pathway^*

Fong-Pin Liang, Chao-Hsiung Lin^¶, Cheng-Deng Kuo^||, Hsueh-Ping Chao, and Shu-Ling Fu^¶1

From the Institute of Traditional Medicine, National Yang-Ming University, 155, Sec. 2, Li-Nong St., Taipei 11221, the Faculty of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, the ^¶Department of Research and Education, Taipei City Hospital, Taipei 10341, and the ^||Department of Research and Education, Veterans General Hospital-Taipei, Taipei 11217, Taiwan

Elevated expression and aberrant activation of the src oncogene are strongly associated with cancer initiation and progression, thereby making Src a promising molecular target for anti-cancer therapy. Through drug screening using a temperature-inducible v-Src-transformed epithelial cell line, we found that andrographolide could suppress v-Src-induced transformation and down-regulate v-Src protein expression. In addition, actin cable dissolution and E-cadherin down-regulation, features of transformed phenotype, are perturbed by andrographolide. Moreover, andrographolide promoted v-Src degradation via a ubiquitin-dependent manner. Although andrographolide treatment altered the tyrosine phosphorylation pattern in v-Src-expressing cells, it did not directly affect the kinase activity of v-Src. Both the Erk and phosphatidylinositol 3-kinase signaling pathways were strongly inhibited in andrographolide-treated v-Src cells. However, only MKK inhibitors (PD98059 and U0126) were able to cause a non-transformed morphology similar to that of andrographolide-treated v-Src cells. Moreover, overexpression of constitutively active MKK1 in v-Src cells blocked andrographolide-mediated morphological inhibition. Interestingly, andrographolide treatment could also reduce the protein level of the c-Src truncation mutant (Src531), an Src mutant originally identified from human colon cancer cells. In summary, we demonstrated that andrographolide antagonized v-Src action through promotion of v-Src protein degradation. Furthermore, attenuation of the Erk1/2 signaling pathway is essential for andrographolide-mediated inhibition of v-Src transformation. Our results demonstrate that andrographolide can act as a v-Src inhibitor and reveal a novel action mechanism of andrographolide.

Received for publication, July 17, 2007 , and in revised form, November 27, 2007.

^* This work was supported by the National Science Council in Taiwan (Grants NSC 93-2320-B-010-067, NSC 95-2627-M-001-005, NSC 96-2317-B-010-001, and NSC 96-2320-B010-028), by Veterans General Hospital-Taipei, Taiwan (Grant V96E2-003), and by the Ministry of Education, Aim for the Top University Plan (Grant 95A-C-D01-PPG-03). 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. S1-S4 and Table S1.

¹ To whom correspondence should be addressed. Tel.: 886-2-2826-7177; Fax: 886-2-2822-5044; E-mail: slfu{at}ym.edu.tw.

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