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Cross-talk between MAP kinase pathways is involved in IGF-independent, IGFBP-6-induced Rh30 rhabdomyosarcoma cell

Ping Fu1, Guang Jun Liang, Sahil S Khot

  • 1Department of Medicine, Central Clinical School, AMREP, Monash University, Melbourne, Victoria, Australia. ping.fu@med.monash.edu.au

Journal of Cellular Physiology
|May 1, 2010
PubMed

Insights

Insulin-like growth factor binding protein-6 (IGFBP-6) can inhibit or promote cancer cell migration. This study reveals IGFBP-6 promotes rhabdomyosarcoma cell migration via MAPK pathways, independent of IGF-II, offering new therapeutic insights.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Insulin-like growth factor binding protein-6 (IGFBP-6) has paradoxical roles in cancer, inhibiting some tumors while promoting others.
  • The mechanisms behind IGFBP-6's contradictory effects on tumorigenicity are not fully understood.
  • A mutant IGFBP-6 (mIGFBP-6) unable to bind IGFs was used to investigate IGF-independent functions.

Purpose of the Study:

  • To elucidate the role of mitogen-activated protein kinase (MAPK) signaling pathways in IGFBP-6-induced migration of Rh30 rhabdomyosarcoma cells.
  • To determine if IGFBP-6's pro-migratory effects are dependent on IGF-II.
  • To understand the cross-talk between MAPK pathways in mediating IGFBP-6's actions.

Main Methods:

  • Utilized wild-type (wt) and mutant IGFBP-6 (mIGFBP-6) in Rh30 rhabdomyosarcoma cell cultures.
  • Investigated the phosphorylation status of ERK1/2, JNK1, p38, and Akt MAPKs.
  • Employed specific inhibitors for ERK1/2, JNK, p38, and Akt pathways to assess their role in cell migration.
  • Distinguished between chemotaxis and chemokinesis using migration assays.

Main Results:

  • mIGFBP-6 induced chemotaxis in Rh30 cells, an IGF-independent process.
  • Both wt-IGFBP-6 and mIGFBP-6 transiently activated ERK1/2 and JNK1, but not p38.
  • Inhibition of ERK1/2 completely blocked migration; JNK inhibition partially blocked it.
  • p38 inhibition blocked ERK1/2 and JNK activation and migration, indicating upstream regulation.
  • ERK1/2 inhibition also suppressed JNK activation, suggesting pathway cross-talk.

Conclusions:

  • IGFBP-6 promotes rhabdomyosarcoma cell migration through an IGF-independent pathway involving MAPK signaling.
  • MAPK pathway cross-talk, particularly involving p38 and ERK1/2, is critical for IGFBP-6-mediated migration.
  • These findings highlight distinct mechanisms for IGFBP-6's effects on cell proliferation (IGF-dependent) and migration (IGF-independent), potentially informing new cancer therapeutics.

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