Impact of the SRC inhibitor dasatinib on the metastatic phenotype of human prostate cancer cells
Impact of the SRC inhibitor dasatinib on the metastatic phenotype of human prostate cancer cells
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DOI：
10.1007/s10585-011-9436-2
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发表时间：
2012-02-01
影响因子：
4
通讯作者：
Siemann, Dietmar W.
中科院分区：
文献类型：
--
作者：
Rice, Lori;Lepler, Sharon;Siemann, Dietmar W.
SRC是一种非受体酪氨酸激酶，在血液以及包括前列腺在内的各种器官的实体瘤中经常过度表达和高度活化，并且与侵袭性疾病和患者预后不良相关。具有发生转移的高风险的前列腺癌患者几乎没有治疗选择，其中没有一种可以导致持久的治愈。因此，本研究的目的是检查SRC抑制剂达沙替尼对人前列腺癌细胞完成转移过程中关键步骤（包括侵袭和血管生成）的能力的影响。达沙替尼治疗通过显著降低改良Boyden小室中的迁移和侵袭，损害了人前列腺癌细胞系PC-3、DU-145和LNCaP的转移表型。还观察到SRC和关键下游信号传导途径元件（包括FAK、STAT 3、桩蛋白和Akt）的磷酸化抑制，并因此增强活化，如通过蛋白质印迹法测定的。这表明达沙替尼干扰与转移级联相关的关键细胞功能。达沙替尼还对微血管内皮细胞在体外形成管的能力有直接影响，并损害PC-3细胞在体内诱导血管生成的能力。总之，本研究结果表明，达沙替尼的SRC抑制可能在减少前列腺癌细胞的转移扩散方面具有实用性。
SRC, a non-receptor tyrosine kinase, is frequently over-expressed and highly activated in blood as well as solid tumors in various organs, including prostate, and has been associated with aggressive disease and a poor patient prognosis. Prostate cancer patients with a high risk of developing metastases have few treatment options, none of which can result in a durable cure. Therefore, the aim of the present study was to examine the impact of a SRC inhibitor, dasatinib, on the ability of human prostate cancer cell to complete key steps in the metastatic process, including invasion and angiogenesis. Dasatinib treatment impaired the metastatic phenotypes of the human prostate cancer cell lines, PC-3, DU-145, and LNCaP, by significantly reducing migration and invasion in modified Boyden chambers. Inhibition of phosphorylation, and therefore enhanced activation, of SRC and key downstream signaling pathway elements, including FAK, STAT3, Paxillin, and Akt, as determined by Western blotting, also was observed. This suggests that dasatinib interferes with critical cell functions associated with the metastatic cascade. Dasatinib also had direct effects on the ability of microvascular endothelial cells to form tubes in vitro and impaired the ability of PC-3 cells to induce angiogenesis in vivo. In conclusion, the present findings suggest that SRC inhibition by dasatinib may have utility in reducing the metastatic spread of prostate cancer cells.