Stromal cell-derived factor-1 enhances motility and integrin up-regulation through CXCR4, ERK and NF-κB-dependent pathway in human lung cancer cells

School of Cosmeceutics, College of Pharmacy, China Medical University, Taichung, Taiwan.
Biochemical Pharmacology (Impact Factor: 5.01). 01/2008; 74(12):1702-12. DOI: 10.1016/j.bcp.2007.08.025
Source: PubMed


The chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor, CXCR4, play a crucial role in adhesion and migration of human cancer cells. Integrins are the major adhesive molecules in mammalian cells. Here we found that SDF-1alpha increased the migration and cell surface expression of beta1 or beta3 integrin in human lung cancer cells (A549 cells). CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited the SDF-1alpha-induced increase in the migration of lung cancer cells. Stimulation of cells with SDF-1alpha caused an increase in extracellular signal regulated kinase (ERK) phosphorylation in a time-dependent manner. In addition, treatment of A549 cells with ERK inhibitor (PD98059), NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited SDF-1alpha-induced cells migration and integrins expression. Treatment of A549 cells with SDF-1alpha induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The SDF-1alpha-mediated increases in IKK alpha/beta phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity were inhibited by PD98059 and ERK2 mutant. Taken together, these results suggest that SDF-1alpha acts through CXCR4 to activate ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of beta1 and beta3 integrins and contributing the migration of lung cancer cell.

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    • "Nuclear factor-kB (NF-kB) transcription factor represents a ubiquitously expressed protein family that modulates the expression of genes implicated in diverse cellular functions, such as stress response, immune reactions and metastasis (Viatour et al., 2005). NF-kB is involved in integrin expression and migration activity in human cancer cells (Huang et al., 2007). "
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    Differentiation 08/2013; 86(1-2):38-47. DOI:10.1016/j.diff.2013.06.005 · 3.44 Impact Factor
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    • "The IL-6 enzyme immunoassay kit was purchased from Cayman Chemical (Ann Arbor, MI). The siCXCR4 and siCXCR4-mut siRNA were generated in our laboratory (siCXCR4 but not siCXCR4-mut specific inhibited the expression of mRNA and protein level of CXCR4) [Huang et al., 2007]. The p38 dominant negative mutant was provided by Dr. J. Han (South-western Medical Center, Dallas, TX). "
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    • "The ability of tumour cells to invade and migrate has been ascribed to the up-regulation of matrix metalloproteases (MMPs) and chemotactic axis CXCR4/SDF-1 [16]. In addition, MAPKs activities have been linked to the regulation of MMPs and CXCR4 [17,18]. Initially, we established that inhibition of MAPKs led to the down-regulation of MMP-2 and CXCR4. "
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    BMC Cancer 03/2010; 10:95. DOI:10.1186/1471-2407-10-95 · 3.36 Impact Factor
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