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Published online before print March 13, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0607397

Received for publication June 13, 2007.
Revised January 2, 2008.
Accepted for publication January 16, 2008.

Article

S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway

Saeid Ghavami ^*, Iran Rashedi ^*, Brian M. Dattilo , Mehdi Eshraghi ^*, Walter J. Chazin , Mohammad Hashemi , Sebastian Wesselborg , Claus Kerkhoff ^||, and Marek Los ^¶@

*Manitoba Institute of Cell Biology and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada; ^||Institute of Experimental Dermatology, Münster, Germany; Departments of Biochemistry and Physics, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA; Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Science, Zahedan, Iran; Department of Internal Medicine I, University of Tübingen, Tübingen, Germany; and ^¶BioApplications Enterprises, Manitoba, Canada

^@ To whom correspondence should be addressed. E-mail: mjelos{at}gmail.com.

	Abstract

The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity against various cells, especially tumor cells. Here, we present evidence that S100A8/A9 also has cell growth-promoting activity at low concentrations. Receptor of advanced glycation end product (RAGE) gene silencing and cotreatment with a RAGE-specific blocking antibody revealed that this activity was mediated via RAGE ligation. To investigate the signaling pathways, MAPK phosphorylation and NF-B activation were characterized in S100A8/A9-treated cells. S100A8/A9 caused a significant increase in p38 MAPK and p44/42 kinase phosphorylation, and the status of stress-activated protein kinase/JNK phosphorylation remained unchanged. Treatment of cells with S100A8/A9 also enhanced NF-B activation. RAGE small interfering RNA pretreatment abrogated the S100A8/A9-induced NF-B activation. Our data indicate that S100A8/A9-promoted cell growth occurs through RAGE signaling and activation of NF-B.

Key Words: NF-B • proliferation

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