Abstract
Aim:
To determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappaB) and promotes oral squamous cell carcinoma (OSCC) invasion.
Methodology:
A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappaB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA).
Results:
We show that the activation of NF-kappaB by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of IkappaBalpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1 alpha mediated invasion of OSCC.
Conclusion:
The CBM complex plays a critical role in CXCR4-induced NF-kappaB activation in OSCC. Targeting molecular components of the NF-kappaB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / physiology*
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B-Cell CLL-Lymphoma 10 Protein
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CARD Signaling Adaptor Proteins / antagonists & inhibitors
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CARD Signaling Adaptor Proteins / physiology*
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Carcinoma, Squamous Cell / pathology*
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Caspase Inhibitors
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Caspases / physiology*
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Cell Line, Tumor
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Chemokine CXCL12 / antagonists & inhibitors
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Chemokine CXCL12 / physiology*
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Enzyme Activation / drug effects
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Gene Silencing
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Genetic Vectors / genetics
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Humans
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I-kappa B Kinase / drug effects
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I-kappa B Proteins / metabolism
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Isoenzymes / antagonists & inhibitors
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Lentivirus / genetics
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / physiology*
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Mouth Neoplasms / pathology*
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / physiology*
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Neoplasm Invasiveness
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / physiology*
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Phosphorylation
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Plasmids / genetics
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Protein Kinase C / antagonists & inhibitors
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Receptors, CXCR4 / physiology
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Adaptor Proteins, Signal Transducing
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B-Cell CLL-Lymphoma 10 Protein
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BCL10 protein, human
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CARD Signaling Adaptor Proteins
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CARD10 protein, human
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CXCL12 protein, human
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CXCR4 protein, human
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Caspase Inhibitors
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Chemokine CXCL12
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I-kappa B Proteins
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Isoenzymes
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Membrane Proteins
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NF-kappa B
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NFKBIA protein, human
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Neoplasm Proteins
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Receptors, CXCR4
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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I-kappa B Kinase
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Protein Kinase C
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Caspases
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MALT1 protein, human
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein