Promotion of cancer cell migration: an insulin-like growth factor (IGF)-independent action of IGF-binding protein-6.

Abstract

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 (Pro(93)/Leu(94)/Leu(97)/Leu(98)) 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.

• Authors: Ping Fu, Julian A Thompson, Leon A Bach
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 31 Pg. 22298-306 (Aug 03 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17519236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Imidazoles
• Insulin-Like Growth Factor Binding Protein 6
• Ligands
• Pyridines
• pyrazolanthrone
• Insulin-Like Growth Factor I
• p38 Mitogen-Activated Protein Kinases
• SB 203580

Topics

• Anthracenes (pharmacology)
• Cell Movement
• Humans
• Imidazoles (pharmacology)
• Insulin-Like Growth Factor Binding Protein 6 (genetics, metabolism)
• Insulin-Like Growth Factor I (metabolism)
• Ligands
• MAP Kinase Signaling System
• Mutation
• Neoplasms (metabolism)
• Protein Binding
• Protein Structure, Tertiary
• Pyridines (pharmacology)
• Rhabdomyosarcoma (metabolism)
• Tumor Cells, Cultured
• p38 Mitogen-Activated Protein Kinases (metabolism)