CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion
CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion
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DOI：
10.1186/1477-7819-9-46
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发表时间：
2011-05-03
影响因子：
3.2
通讯作者：
Singh, Shailesh
中科院分区：
文献类型：
--
作者：
Johnson-Holiday, Crystal;Singh, Rajesh;Singh, Shailesh
背景：化疗在很大程度上依赖于凋亡来杀死乳腺癌（BrCa）细胞。许多乳腺肿瘤对化疗有反应，但在这种初始反应中存活下来的细胞对后续治疗产生抗性。这导致具有增强的迁移、侵入和在次级位点存活的能力的侵袭性细胞变体。转移和化疗耐药性是大多数癌症相关死亡的原因;因此，非常需要旨在最大限度地减少两者的治疗。我们最近发现CCR 9-CCL 25相互作用促进BrCa细胞迁移和侵袭，而其他人已经表明该轴在T细胞存活中起重要作用。方法：采用BrdU掺入法、Vybrant细胞凋亡检测和TUNEL法检测CCR 9-CCL 25轴在顺铂诱导的乳腺癌细胞凋亡中的作用。使用快速活化细胞ELISA（FACE）测定来定量在存在或不存在CCL 25的情况下，在有或没有顺铂处理的乳腺癌细胞中PI 3 K（p85）、Akt（Ser 473）、GSK-3 β（Ser 9）和FKHRThr 24的原位活化。CCR 9-CCL 25轴为BrCa细胞提供生存优势，并抑制顺铂诱导的PI 3 K依赖性和粘着斑激酶（FAK）凋亡。独立时尚此外，CCR 9-CCL 25轴通过Akt和随后的糖原合成酶激酶-3 β（GSK-3 β）和人类横纹肌肉瘤（FKHR）失活中的叉头激活细胞存活信号。这些结果表明，CCR 9-CCL 25轴主要通过PI 3 K/Akt依赖方式在BrCa细胞存活和顺铂的低化疗疗效中起重要作用。
Background: Chemotherapy heavily relies on apoptosis to kill breast cancer (BrCa) cells. Many breast tumors respond to chemotherapy, but cells that survive this initial response gain resistance to subsequent treatments. This leads to aggressive cell variants with an enhanced ability to migrate, invade and survive at secondary sites. Metastasis and chemoresistance are responsible for most cancer-related deaths; hence, therapies designed to minimize both are greatly needed. We have recently shown that CCR9-CCL25 interactions promote BrCa cell migration and invasion, while others have shown that this axis play important role in T cell survival. In this study we have shown potential role of CCR9-CCL25 axis in breast cancer cell survival and therapeutic efficacy of cisplatin.Methods: Bromodeoxyuridine (BrdU) incorporation, Vybrant apoptosis and TUNEL assays were performed to ascertain the role of CCR9-CCL25 axis in cisplatin-induced apoptosis of BrCa cells. Fast Activated Cell-based ELISA (FACE) assay was used to quantify In situ activation of PI3K(p85), Akt(Ser473), GSK-3 beta(Ser9) and FKHRThr24 in breast cancer cells with or without cisplatin treatment in presence or absence of CCL25.Results: CCR9-CCL25 axis provides survival advantage to BrCa cells and inhibits cisplatin-induced apoptosis in a PI3K-dependent and focal adhesion kinase (FAK)-independent fashion. Furthermore, CCR9-CCL25 axis activates cell-survival signals through Akt and subsequent glycogen synthase kinase-3 beta (GSK-3 beta) and forkhead in human rhabdomyosarcoma (FKHR) inactivation. These results show that CCR9-CCL25 axis play important role in BrCa cell survival and low chemotherapeutic efficacy of cisplatin primarily through PI3K/Akt dependent fashion.