Cross-talk between MAP kinase pathways is involved in IGF-independent, IGFBP-6-induced Rh30 rhabdomyosarcoma cell migration
(c) 2010 Wiley-Liss, Inc..
Insulin-like growth factor binding protein-6 (IGFBP-6) inhibits the tumorigenic properties of IGF-II-dependent cancer cells by directly inhibiting IGF-II actions. However, in some cases, IGFBP-6 is associated with increased cancer cell tumorigenicity, which is unlikely to be due to IGF-II inhibition. The mechanisms underlying the contradictory actions of IGFBP-6 remain unclear. We recently generated an IGFBP-6 mutant that does not bind IGFs (mIGFBP-6) to address this issue. Although RD rhabdomyosarcoma cells express IGF-II, we previously showed that mIGFBP-6 promoted migration through an IGF-independent, p38-dependent pathway. We further studied the role of MAP kinases in IGFBP-6-induced migration of Rh30 rhabdomyosarcoma cells, which also express IGF-II. In these cells, mIGFBP-6 induced chemotaxis rather than chemokinesis. Both wild-type (wt) and mIGFBP-6 transiently induced phosphorylation of ERK1/2 and JNK1, but not p38. Inhibition of ERK1/2 phosphorylation completely prevented mIGFBP-6-induced ERK1/2 activation and cell migration, whereas a JNK inhibitor partially prevented migration. Interestingly, p38 pathway inhibition completely prevented mIGFBP-6-induced ERK1/2 and JNK1 activation and migration despite mIGFBP-6 not activating p38. Furthermore, blocking the ERK1/2 pathway also inhibited mIGFBP-6-induced JNK1 activation. In contrast, IGFBP-6 had no effect on Akt phosphorylation and an Akt inhibitor had no effect on migration. These results indicate that IGFBP-6 promotes Rh30 rhabdomyosarcoma chemotaxis in an IGF-independent manner, and that MAPK signaling pathways and their cross-talk play an important role in this process. Therefore, besides decreasing Rh30 cell proliferation by inhibiting IGF-II, IGFBP-6 promotes their migration via a distinct pathway. Understanding these disparate actions of IGFBP-6 may lead to the development of novel cancer therapeutics.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2010 |
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| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:224 |
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| Enthalten in: |
Journal of cellular physiology - 224(2010), 3 vom: 01. Sept., Seite 636-43 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fu, Ping [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.08.2010 Date Revised 18.11.2010 published: Print Citation Status MEDLINE |
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| doi: |
10.1002/jcp.22156 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM197732178 |
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| 520 | |a (c) 2010 Wiley-Liss, Inc. | ||
| 520 | |a Insulin-like growth factor binding protein-6 (IGFBP-6) inhibits the tumorigenic properties of IGF-II-dependent cancer cells by directly inhibiting IGF-II actions. However, in some cases, IGFBP-6 is associated with increased cancer cell tumorigenicity, which is unlikely to be due to IGF-II inhibition. The mechanisms underlying the contradictory actions of IGFBP-6 remain unclear. We recently generated an IGFBP-6 mutant that does not bind IGFs (mIGFBP-6) to address this issue. Although RD rhabdomyosarcoma cells express IGF-II, we previously showed that mIGFBP-6 promoted migration through an IGF-independent, p38-dependent pathway. We further studied the role of MAP kinases in IGFBP-6-induced migration of Rh30 rhabdomyosarcoma cells, which also express IGF-II. In these cells, mIGFBP-6 induced chemotaxis rather than chemokinesis. Both wild-type (wt) and mIGFBP-6 transiently induced phosphorylation of ERK1/2 and JNK1, but not p38. Inhibition of ERK1/2 phosphorylation completely prevented mIGFBP-6-induced ERK1/2 activation and cell migration, whereas a JNK inhibitor partially prevented migration. Interestingly, p38 pathway inhibition completely prevented mIGFBP-6-induced ERK1/2 and JNK1 activation and migration despite mIGFBP-6 not activating p38. Furthermore, blocking the ERK1/2 pathway also inhibited mIGFBP-6-induced JNK1 activation. In contrast, IGFBP-6 had no effect on Akt phosphorylation and an Akt inhibitor had no effect on migration. These results indicate that IGFBP-6 promotes Rh30 rhabdomyosarcoma chemotaxis in an IGF-independent manner, and that MAPK signaling pathways and their cross-talk play an important role in this process. Therefore, besides decreasing Rh30 cell proliferation by inhibiting IGF-II, IGFBP-6 promotes their migration via a distinct pathway. Understanding these disparate actions of IGFBP-6 may lead to the development of novel cancer therapeutics | ||
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