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A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase
被引:162
作者:

Collins, CS
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机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

Hong, JY
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h-index: 0
机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

Sapinoso, L
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h-index: 0
机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

Zhou, YY
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h-index: 0
机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

Liu, Z
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机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

Micklash, K
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机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

Schultz, PG
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机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

Hampton, GM
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h-index: 0
机构: Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
机构:
[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
[2] Scripps Res Inst, Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA
来源:
关键词:
automated;
RNA interference;
D O I:
10.1073/pnas.0600040103
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
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.
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页码:3775 / 3780
页数:6
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