Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration.
Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an essential role in protease-mediated extracellular matrix (ECM) degradation, but it also functions as a sheddase releasing non-ECM substrates such as receptor activator of NF-kappaB ligand (RANKL), an osteoclastogenic factor typically confined to the surface of osteoblasts. We previously found high expression of MT1-MMP in skeletal metastasis of prostate cancer patients, in a pattern similar to RANKL expression. We also showed that overexpression of MT1-MMP in prostate cancer cells increases tumor growth and osteolysis in an intratibial mouse model of bone metastasis, and that soluble factor(s) shed by tumor-derived MT1-MMP enhance osteoclast differentiation in a RANKL-dependent manner. Recent evidence indicates that the cognate receptor for RANKL, RANK, is expressed in prostate cancer cells, suggesting the presence of an autocrine pathway. In this study, we show that MT1-MMP-expressing LNCaP prostate cancer cells display enhanced migration. Moreover, conditioned medium from LNCaP cells expressing both RANKL and MT1-MMP stimulates the migration of MT1-MMP-deficient C42b prostate cancer cells. This enhanced chemotaxis can be abrogated by osteoprotegerin (soluble decoy receptor of RANKL), MIK-G2 (a selective inhibitor for MT1-MMP), and PP2 (a Src inhibitor). These findings indicate that tumor-derived MT1-MMP enhances tumor cell migration through initiation of an autocrine loop requiring ectodomain shedding of membrane-bound RANKL in prostate cancer cells, and that Src is a key downstream mediator of RANKL-induced migration of prostate cancer cells.
Sabbota
Aaron L
AL
Department of Urology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Kim
Hyeong-Reh Choi
HR
Zhe
Xiaoning
X
Fridman
Rafael
R
Bonfil
R Daniel
RD
Cher
Michael L
ML
D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand / Q000378:metabolism*; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
D053245:RANK Ligand; C505688:TNFSF11 protein, human; D019061:src-Family Kinases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14