title: Proteinase-activated receptors 1 and 2 regulate invasive behavior of human melanoma cells via activation of protein kinase D1.
abstract: Recent studies have indicated an important role of proteinases and proteinase-activated receptors (PARs) in tumorigenesis. Although a role for PARs has been described in various skin tumors including melanoma, the underlying cellular mechanisms have not been understood. Recent studies have suggested PAR(1) as a regulator of melanoma cell growth and metastasis by affecting angiogenic and invasive factors. Moreover, changes in the expression patterns of PAR(1) and PAR(2) correlate with skin cancer progression, and PAR(1) is overexpressed in melanoma. Therefore, we sought to elucidate the putative role of PAR(1)- and PAR(2)-mediated signal transduction pathways during melanoma progression. Activation of both PAR(1) and PAR(2) led to rapid phosphorylation of protein kinase D1 (PKD1) in cultured WM9 melanoma cells. PKD1 is known to be involved in cell migration, integrin regulation, and intracellular vesicle transport. Downregulation of PKD1 by siRNA resulted in diminished proliferation, decreased αvβ3 integrin regulation, and secretion of pro-angiogenic chemokine IL-8 in WM9 cells. In conclusion, our results show that PAR(1) and PAR(2) are involved in WM9 cell proliferation and secretion of IL-8 by activation of PKD1. Inactivation of the PKD1 pathway may be beneficial for the inhibition of PAR-induced melanoma proliferation and for maintenance of the inflammatory tumor environment.
authors: Department of Dermatology and IZKF Münster, University of Münster, Münster, Germany.
authors: Cordula
authors: C
authors: Kempkes
authors: Anke
authors: A
authors: Rattenholl
authors: Jörg
authors: J
authors: Buddenkotte
authors: Elwira
authors: E
authors: Strozyk
authors: Jürgen
authors: J
authors: Eberle
authors: Angelika
authors: A
authors: Hausser
authors: Ferda
authors: F
authors: Cevikbas
authors: Stefan W
authors: SW
authors: Schneider
authors: Martin
authors: M
authors: Steinhoff
mesh_terms: D045744:Cell Line, Tumor; D048430:Cell Shape; D004789:Enzyme Activation; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000473:pathology*; D010766:Phosphorylation; D044463:Receptor, PAR-1 / Q000502:physiology*; D044464:Receptor, PAR-2 / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology*; D050396:TRPP Cation Channels / Q000502:physiology*
chemical_list: D039302:Integrin alphaVbeta3; D016209:Interleukin-8; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D050396:TRPP Cation Channels