Involvement of integrin up-regulation in RANKL/RANK pathway of chondrosarcomas migration.
Invasion of tumor cells is the primary cause of therapeutic failure in malignant chondrosarcomas treatment. Receptor activator of nuclear factor-kappaB ligand (RANKL) and its receptor, RANK, play a key roles in osteoclastogenesis and tumor metastasis. We found that the RANKL and RANK expression in human chondrosarcoma tissues was higher than that in normal cartilage. We also found that RANKL directed the migration and increased cell surface expression of beta1 integrin in human chondrosarcoma cells (JJ012 cells). Pretreatment of JJ012 cells with MAPK kinase (MEK) inhibitors, PD98059 or U0126, inhibited the RANKL-induced migration and integrin expression. Stimulation of cells with RANKL increased the phosphorylation of MEK and extracellular signal-regulating kinase (ERK). In addition, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited RANKL-induced cells migration and integrin up-regulation. Taken together, these results suggest that the RANKL acts through MEK/ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activation of beta1 integrin and contributing to the migration of human chondrosarcoma cells.
Hsu
Chin-Jung
CJ
School of Chinese Medicine, China Medical University, Taichung, Taiwan.
Lin
Tsang-Yu
TY
Kuo
Chien-Chung
CC
Tsai
Chun-Hao
CH
Lin
Mou-Zen
MZ
Hsu
Horng-Chaung
HC
Fong
Yi-Chin
YC
Tang
Chih-Hsin
CH
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002813:Chondrosarcoma / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
D016023:Integrins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases