NDLI: Shedding of RANKL by Tumor-Associated MT1-MMP Activates Src-dependent Prostate Cancer Cell Migration

Content Provider	PubMed Central
Author	Sabbota, Aaron L. Kim, Hyeong-reh Choi Zhe, Xiaoning Fridman, Rafael Daniel, Bonfil R. Cher, Michael L.
Abstract	Membrane type-I 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-κB 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 (PC) patients, in a pattern similar to RANKL expression. We also showed that overexpression of MT1-MMP in PC 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 PC cells, suggesting the presence of an autocrine pathway. In this study, we show that MT1-MMP-expressing LNCaP PC cells display enhanced migration. Moreover, conditioned medium from LNCaP cells expressing both RANKL and MT1-MMP stimulates the migration of MT1-MMP-deficient C42b PC 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 via initiation of an autocrine loop requiring ectodomain shedding of membrane-bound RANKL in PC cells, and that Src is a key downstream mediator of RANKL-induced migration of PC cells.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-4416
Ending Page	5566
Page Count	9
Starting Page	5558
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	13
Volume Number	70
Language	English
Publisher Date	2010-07-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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