TAK1-TAB2 signaling contributes to bone destruction by breast carcinoma cells.
TAK1-TAB2 signaling contributes to bone destruction by breast carcinoma cells.
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TAK1-TAB2信号传导有助于乳腺癌细胞破坏骨骼。
DOI：
10.1158/1541-7786.mcr-10-0196
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Bakin AV
中科院分区：
文献类型：
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作者：
Safina A;Sotomayor P;Limoge M;Morrison C;Bakin AV
晚期乳腺癌经常转移到骨骼并导致骨骼破坏，但其潜在机制尚未完全了解。这项研究提供的证据表明，肿瘤细胞中的TGF-β活化蛋白激酶1（TAK 1）信号转导促进了转移性乳腺癌细胞的骨破坏，控制了促转移因子（包括MMP-9和COX 2）的表达。乳腺癌MDA-MB-231细胞中显性阴性（dn）TAK 1对TAK 1信号传导的抑制损害了心内注射模型中癌细胞的骨定植和骨溶解。机制研究表明，通过dn-TAK 1或siRNA抑制TAK 1可阻断与骨转移相关的因子如MMP-9、COX 2/PTGS 2、PTHrP和IL 8的表达，但不影响TGF-β对p38 MAPK的激活。TAK 1信号传导由TAK 1结合伴侣TAB 1、TAB 2和TAB 3介导。癌细胞表达升高的TAB 2和TAB 3的mRNA水平，而TAB 1的表达明显低。因此，通过siRNA消耗TAB 2降低MMP-9和COX 2的表达。总之，这些研究表明，TAK 1-TAB 2/TAB 3信号传导轴对于癌诱导的骨病变至关重要，介导促侵袭因子和溶骨性因子的表达。这些发现将TAK 1-TAB 2轴确定为骨转移的潜在治疗靶点。
Advanced-stage breast cancers frequently metastasize to the bones and cause bone destruction, but the underlying mechanism is not fully understood. This study presents evidence that TGF-β-activated protein kinase 1 (TAK1) signaling in tumor cells promotes bone destruction by metastatic breast carcinoma cells, controlling expression of pro-metastatic factors, including MMP-9 and COX2. Suppression of TAK1 signaling by dominant-negative (dn) TAK1 in breast carcinoma MDA-MB-231 cells impairs bone colonization by carcinoma cells and bone osteolysis in the intra-cardiac injection model. Mechanistic studies showed that inhibition of TAK1 by dn-TAK1 or siRNA blocked expression of factors implicated in bone metastasis, such as MMP-9, COX2/PTGS2, PTHrP, and IL8, but did not affect activation of p38MAPK by TGF-β. TAK1 signaling is mediated by TAK1-binding partners TAB1, TAB2 and TAB3. Carcinoma cells express elevated mRNA levels of TAB2 and TAB3, whereas the TAB1 expression is noticeably low. Accordingly, depletion of TAB2 by siRNA reduced expression of MMP-9 and COX2. Together, these studies demonstrate that the TAK1-TAB2/TAB3 signaling axis is critical for carcinoma-induced bone lesions, mediating expression of pro-invasive and osteolytic factors. These findings identify the TAK1-TAB2 axis as a potential therapeutic target in bone metastasis.