Cross-talk between MAP kinase pathways is involved in IGF-independent, IGFBP-6-induced Rh30 rhabdomyosarcoma cell migration.
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.
Fu
Ping
P
Department of Medicine, Central Clinical School, AMREP, Monash University, Melbourne, Victoria, Australia. ping.fu@med.monash.edu.au
Liang
Guang Jun
GJ
Khot
Sahil S
SS
Phan
Robert
R
Bach
Leon A
LA
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D018976:Insulin-Like Growth Factor Binding Protein 6; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D048056:Mitogen-Activated Protein Kinase 9; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases