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J. Biol. Chem., Vol. 282, Issue 31, 22298-22306, August 3, 2007

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Promotion of Cancer Cell Migration

AN INSULIN-LIKE GROWTH FACTOR (IGF)-INDEPENDENT ACTION OF IGF-BINDING PROTEIN-6^*

Ping Fu¹, Julian A. Thompson, and Leon A. Bach

From the Department of Medicine, Central and Eastern Clinical School, Faculty of Medicine, Nursing, and Health Sciences, Alfred Medical Research and Education Precinct, Monash University, Prahran Victoria 3181 and the Department of Endocrinology and Diabetes, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia

A family of six high affinity IGF-binding proteins (IGFBPs 1–6) plays an important role in modulating IGF activities. Recent studies suggest that some IGFBPs may have IGF-independent effects, including induction of apoptosis and modulation of cell migration. However, very little is known about possible IGF-independent actions of IGFBP-6. We have generated a non-IGF-binding IGFBP-6 mutant by substituting Ala for four amino acid residues (Pro⁹³/Leu⁹⁴/Leu⁹⁷/Leu⁹⁸) in its N-domain IGF-binding site. A >10,000-fold loss of binding affinity for IGF-I and IGF-II was observed using charcoal solution binding assay, BIAcore biosensor, and ligand blotting. Wild-type and mutant IGFBP-6, as well as IGF-II, induced cell migration in RD rhabdomyosarcoma and LIM 1215 colon cancer cells. Cell migration was mediated by the C-domain of IGFBP-6. Transient p38 phosphorylation was observed in RD cells after treatment with IGFBP-6, whereas no change was seen in phospho-ERK1/2 levels. Phospho-JNK was not detected. IGFBP-6-induced cell migration was inhibited by SB203580, an inhibitor of p38 MAPK, and PD98059, an inhibitor of ERK1/2 MAPK activation. In contrast, SP600125, a JNK MAPK inhibitor, had no effect on migration. Knockdown of p38 MAPK using short interfering RNA blocked IGFBP-6-induced migration of RD cells. These results indicate that p38 MAPK is involved in IGFBP-6-induced IGF-independent RD cell migration.

Received for publication, April 11, 2007 , and in revised form, May 21, 2007.

^* This work was supported by Grant 299960 from the National Health and Medical Research Council of Australia and a grant from the Cancer Council of Victoria. 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.

¹ To whom correspondence should be addressed. Tel.: 613-9903-0676; Fax: 613-9903-0318; E-mail: ping.fu{at}med.monash.edu.au.

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