Onodera Yasuhito, Hashimoto Shigeru, Hashimoto Ari, Morishige Masaki, Mazaki Yuichi, Yamada Atsuko, Ogawa Eiji, Adachi Masashi, Sakurai Takaki, Manabe Toshiaki, Wada Hiromi, Matsuura Nariaki, Sabe Hisataka
Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka, Japan.
EMBO J. 2005 Mar 9;24(5):963-73. doi: 10.1038/sj.emboj.7600588. Epub 2005 Feb 17.
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.
鉴定在癌症侵袭中发挥作用但在正常成年细胞中不发挥作用的分子机制，将极大地推动癌症治疗。在此，我们发现一种ArfGAP，即AMAP1/PAG2，在高侵袭性乳腺癌细胞中高表达，但在非侵袭性乳腺癌细胞和正常乳腺上皮细胞中低表达。siRNA介导的AMAP1沉默有效阻断了侵袭活性。AMAP1在人乳腺原发性肿瘤中的表达也表明其与恶性肿瘤的潜在相关性。桩蛋白（paxillin）和皮层肌动蛋白（cortactin）已被证明在侵袭性伪足中共定位，并在乳腺癌侵袭中起关键作用。我们发现AMAP1也定位于侵袭性伪足，并且起到连接桩蛋白和皮层肌动蛋白的作用。这种AMAP1介导的三聚体蛋白复合物仅在侵袭性癌细胞中被检测到，阻断这种复合物的形成可有效抑制其体外侵袭活性和在小鼠体内的转移。我们的结果表明，AMAP1是参与不同乳腺癌侵袭活性的一个成分，并为预防乳腺癌侵袭和转移的可能治疗靶点提供了新信息。
