Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration.
Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration.
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DOI：
10.1158/0008-5472.can-09-4416
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发表时间：
2010-07-01
期刊：
影响因子：
11.2
通讯作者：
Cher ML
中科院分区：
文献类型：
--
作者：
Sabbota AL;Kim HR;Zhe X;Fridman R;Bonfil RD;Cher ML
膜型基质金属蛋白酶在蛋白水解酶介导的细胞外基质降解过程中起重要作用，但它也可以释放非细胞外基质底物，如核因子受体激活剂B配体(RANKL)，这是一种典型地局限于成骨细胞表面的破骨细胞因子。我们先前在前列腺癌(PC)患者的骨转移中发现MT1-MMP高表达，其表达模式与RANKL相似。我们还发现，在骨内转移的小鼠骨转移模型中，在PC细胞中过表达MT1-MMP会增加肿瘤的生长和骨溶解，并且肿瘤来源的Mt1-MMPs释放的可溶性因子/S以RANKL依赖的方式促进破骨细胞的分化。最近的证据表明，RANKL的同源受体RANKL在PC细胞中表达，提示存在自分泌途径。在这项研究中，我们发现表达MT1-MMP的LNCaP PC细胞表现出增强的迁移能力。此外，同时表达RANKL和MT1-基质金属蛋白酶的LNCaP细胞的条件培养液可以刺激MT1-基质金属蛋白酶缺陷的C42b PC细胞的迁移。这种增强的趋化作用可以被护骨素(RANKL的可溶性诱骗受体)、MIK-G2(MT1-MMPs的选择性抑制剂)和PP2(Src抑制剂)所消除。这些发现表明，肿瘤来源的MT1-MMP通过启动需要膜结合的RANKL在PC细胞中的胞外脱落的自分泌环路来促进肿瘤细胞的迁移，而Src是RANKL诱导的PC细胞迁移的关键下游介质。
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.