PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.
PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.
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DOI：
10.1016/j.canlet.2016.07.017
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发表时间：
2016-10-01
期刊：
影响因子：
9.7
通讯作者：
Lambert JR
中科院分区：
文献类型：
--
作者：
Gari HH;DeGala GD;Ray R;Lucia MS;Lambert JR
三阴性乳腺癌(TNBCs)是最具侵袭性的癌症之一，其特点是具有高侵袭、转移和复发的倾向。我们先前报道，TNBC特异性抑制剂AMPI-109通过降低转移促进磷酸酶PRL-3的水平，显著削弱TNBC细胞的迁移和侵袭能力。在这里，我们研究了AMPI-109和PRL-3的缺失阻碍细胞迁移和侵袭的机制。AMPI-109处理或下调PRL-3表达与Src和ERK信号失活以及伴随的RhoA和rac1/2/3 GTPase蛋白水平下调有关。这些细胞变化导致重新排列的丝状肌动蛋白网络，这是细胞迁移和入侵所必需的。相反，PRL-3的过表达通过上调基质金属蛋白酶10促进TNBC细胞的侵袭，导致TNBC细胞对主要基底膜成分层粘连蛋白的黏附和降解。我们的数据表明，PRL-3参与了TNBC细胞的焦点黏附途径，这是促进TNBC细胞迁移和侵袭的关键机制。总之，这些数据表明，阻断PRL-3活性可能是降低TNBC细胞转移潜能的有效方法。
Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells.