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Glial cell-derived neurotrophic factor increases migration of human chondrosarcoma cells via ERK and NF-kappaB
Chen-Ming Su1, Dah-Yuu Lu, Chin-Jung Hsu
1Graduate Institute of Sports and Health, National Changhua University of Education, Changhua County, Taiwan.
Abstract:
Invasion of tumor cells is the primary cause of therapeutic failure in the treatment of malignant chondrosarcomas. Glial cell-derived neurotrophic factor (GDNF) plays a crucial role in migration and metastasis of human cancer cells. Integrins are the major adhesive molecules in mammalian cells. Here we found that GDNF directed the migration and increased cell surface expression of alphav and beta3 integrin in human chondrosarcoma cells. Pretreated of JJ012 cells with MAPK kinase (MEK) inhibitors PD98059 or U0126 inhibited the GDNF-mediated migration and integrin expression. Stimulation of cells with GDNF increased the phosphorylation of MEK and extracellular signal-regulating kinase (ERK). In addition, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited GDNF-mediated cells migration and integrin up-regulation. Stimulation of cells with GDNF induced IkappaB kinase (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the GDNF-mediated increasing of kappaB-luciferase activity was inhibited by PD98059, U0126, PDTC and TPCK or MEK, ERK, IKKalpha, and IKKbeta mutants. Taken together, these results suggest that the GDNF acts through MEK/ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of alphavbeta3 integrin and contributing the migration of human chondrosarcoma cells.
Insights
Glial cell-derived neurotrophic factor (GDNF) promotes chondrosarcoma cell migration by activating MEK/ERK and NF-kappaB pathways. This leads to increased alphavbeta3 integrin expression, driving tumor cell invasion and therapeutic failure.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Tumor cell invasion is a key factor in chondrosarcoma treatment failure.
- Glial cell-derived neurotrophic factor (GDNF) is implicated in cancer cell migration and metastasis.
- Integrins are critical adhesion molecules involved in cell migration.
Purpose of the Study:
- To investigate the role of GDNF in human chondrosarcoma cell migration.
- To elucidate the molecular pathways involved in GDNF-mediated migration and integrin expression.
Main Methods:
- Human chondrosarcoma cells (JJ012) were treated with GDNF.
- Inhibitors of MAPK kinase (MEK), extracellular signal-regulated kinase (ERK), and NF-kappaB were used.
- Cell surface integrin expression and phosphorylation of signaling proteins were analyzed.
Main Results:
- GDNF increased chondrosarcoma cell migration and cell surface expression of alphavbeta3 integrin.
- MEK/ERK and NF-kappaB signaling pathways were activated by GDNF.
- Inhibiting MEK/ERK or NF-kappaB blocked GDNF-induced migration and integrin expression.
Conclusions:
- GDNF promotes human chondrosarcoma cell migration via the MEK/ERK pathway, which activates IKKalpha/beta and NF-kappaB.
- This activation leads to increased alphavbeta3 integrin expression, contributing to tumor cell invasion.
- Targeting the GDNF-MEK/ERK-NF-kappaB-integrin axis may offer therapeutic strategies for chondrosarcomas.
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