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Cross-Talk Between MAP Kinase Pathways Is Involved in IGF-Independent, IGFBP-6-Induced Rh30 Rhabdomyosarcoma Cell Migration
被引:23
作者:
Fu, Ping
[1
]
Liang, Guang Jun
[1
]
Khot, Sahil S.
[1
]
Phan, Robert
[1
]
Bach, Leon A.
[1
,2
]
机构:
[1] Monash Univ, Dept Med, Cent Clin Sch, AMREP, Melbourne, Vic 3004, Australia
[2] The Alfred, Dept Endocrinol & Diabet, Melbourne, Vic, Australia
基金:
英国医学研究理事会;
关键词:
INSULIN-LIKE-GROWTH;
ACTIVATED PROTEIN-KINASE;
COLON-CANCER CELLS;
BINDING PROTEIN-6;
IN-VIVO;
PLASMINOGEN-ACTIVATOR;
SIGNALING PATHWAYS;
JNK;
CHEMOTAXIS;
EXPRESSION;
D O I:
10.1002/jcp.22156
中图分类号:
Q2 [细胞生物学];
学科分类号:
071009 ;
090102 ;
摘要:
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. © 2010 Wiley-Liss, Inc.
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页码:636 / 643
页数:8
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