Melanoma cell migration to type IV collagen requires activation of NF-kappaB.
Chemotaxis is the consequence of environmental factors engaging their receptors to initiate signaling cascades. However, the biochemical mechanisms controlling this phenomenon are not clear. We employed an in vitro modified Boyden 48-well chemotaxis migration system to characterize the role of signal transducers in type IV collagen (CIV) induced A2058 human melanoma cell migration. Using specific pharmacological inhibitors and a series of dominant-negative and constitutively active signaling proteins, we show that Ras and Rac GTPases, PI-3K, and PKC participate in cell migration mediated by beta1 integrins. Collagen also induces a time- dependent degradation of IkappaB-alpha and an increase in nuclear translocation of NF-kappaB which is dependent on PKC pathway. More importantly, collagen-stimulated melanoma cell migration directly correlated with an increase in NF-kappaB transactivation. Furthermore, CIV induced an increase in beta1 integrin mRNA levels. Specific NF-kappaB inhibitors Helenalin and SN-50 inhibited melanoma cell migration to collagen, indicating a novel requirement for NF-kappaB transactivation in cell chemotaxis mediated by beta1 integrin signals. These results describe signal transduction events that are initiated by type IV collagen through beta1 integrins and demonstrate an important role for NF-kappaB in regulating melanoma chemotaxis.
Hodgson
Louis
L
Department of Bioengineering, The Pennsylvania State University, University Park 16802, USA.
Henderson
Andrew J
AJ
Dong
Cheng
C
D001483:Base Sequence; D002465:Cell Movement; D024141:Collagen Type IV / Q000378:metabolism* / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics; D008545:Melanoma / Q000473:pathology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured
D024141:Collagen Type IV; D019012:Integrin beta1; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020558:GTP Phosphohydrolases