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A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase.

Collins, Cynthia S and Hong, Jiyong and Sapinoso, Lisa and Zhou, Yingyao and Liu, Zheng and Micklash, Kenneth and Schultz, Peter G and Hampton, Garret M (2006) A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proceedings of the National Academy of Sciences of the United States of America, 103 (10). pp. 3775-3780. ISSN 0027-8424

Abstract

Cell motility is a complex biological process, involved in development, inflammation, homeostasis, and pathological processes such as the invasion and metastatic spread of cancer. Here, we describe a genomic screen designed to identify inhibitors of cell migration. A library of 10,996 small interfering RNAs (targeting 5,234 human genes) was screened for their ability to block the migration of a highly motile ovarian carcinoma cell line, SKOV-3, by using a 384-well wound-healing assay coupled with automated microscopy and wound quantification. Two or more small interfering RNAs against four genes, CDK7, DYRK1B, MAP4K4 (NIK/HGK) (MAP4K4, mitogen-activated protein 4 kinase 4), and SCCA-1 (SerpinB3), potently blocked the migration of SKOV-3 cells, concordant with reduced transcript levels. Further studies of the promigratory role of MAP4K4 showed that the knockdown of this transcript inhibited the migration of multiple carcinoma cell lines, indicating a broad role in cell motility and potently suppressed the invasion of SKOV-3 cells in vitro. The effect of MAP4K4 on cellular migration was found to be mediated through c-Jun N-terminal kinase, independent of AP1 activation and downstream transcription. Accordingly, small molecule inhibition of c-Jun N-terminal kinase suppressed SKOV-3 cell migration, underscoring the potential therapeutic utility of mitogen-activated protein kinase pathway inhibition in cancer progression.

Item Type: Article
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Additional Information: free full text available at publisher's official URL and at PubMedCentral; author can archive post-print (ie final draft post-refereeing);
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Date Deposited: 14 Dec 2009 14:04
Last Modified: 14 Dec 2009 14:04
URI: https://oak.novartis.com/id/eprint/154

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