Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities
Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities
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DOI：
10.1038/sj.emboj.7600588
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发表时间：
2005-03-09
期刊：
影响因子：
11.4
通讯作者：
Sabe, H
中科院分区：
文献类型：
--
作者：
Onodera, Y;Hashimoto, S;Sabe, H
鉴定在癌症侵袭中使用的分子机制，而不是在正常的成体细胞中，将大大有助于癌症治疗。在这里，我们发现ArfGAP，AMAP 1/PAG 2，在高度侵袭性乳腺癌细胞中以高水平表达，但在非侵袭性乳腺癌细胞和正常乳腺上皮细胞中以非常低的水平表达。siRNA介导的AMAP 1沉默有效地阻断了入侵活动。AMAP 1在人乳腺原发性肿瘤中的表达也表明其与恶性程度的潜在相关性。桩蛋白和coronin已被证明共定位于侵袭伪足，并在乳腺癌侵袭中发挥关键作用。我们发现AMAP 1也定位于侵入伪足，并起到桥接桩蛋白和corprin的作用。这种AMAP 1介导的三聚体蛋白复合物仅在侵袭性癌细胞中检测到，阻断这种复合物的形成有效地抑制了它们在体外的侵袭活性和在小鼠中的转移。我们的研究结果表明，AMAP 1是参与不同的乳腺癌的侵袭活动的一个组成部分，并提供了新的信息，为预防乳腺癌的侵袭和转移的可能的治疗靶点。
Identification of the molecular machinery employed in cancer invasion, but not in normal adult cells, will greatly contribute to cancer therapeutics. Here we found that an ArfGAP, AMAP1/PAG2, is expressed at high levels in highly invasive breast cancer cells, but at very low levels in noninvasive breast cancer cells and normal mammary epithelial cells. siRNA-mediated silencing of AMAP1 effectively blocked the invasive activities. AMAP1 expression in human breast primary tumors also indicated its potential correlation with malignancy. Paxillin and cortactin have been shown to colocalize at invadopodia and play a pivotal role in breast cancer invasion. We found that AMAP1 is also localized at invadopodia, and acts to bridge paxillin and cortactin. This AMAP1-mediated trimeric protein complex was detected only in invasive cancer cells, and blocking this complex formation effectively inhibited their invasive activities in vitro and metastasis in mice. Our results indicate that AMAP1 is a component involved in invasive activities of different breast cancers, and provide new information regarding the possible therapeutic targets for prevention of breast cancer invasion and metastasis.