Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA.
J Ovarian Res. 2010 Jun 17;3:15. doi: 10.1186/1757-2215-3-15.
Cisplatin is more often used to treat ovarian cancer (OvCa), which provides modest survival advantage primarily due to chemo-resistance and up regulated anti-apoptotic machineries in OvCa cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in OvCa cell may improve therapeutic outcomes. We have shown that ovarian cancer cells express CC chemokine receptor-9 (CCR9). Others have also shown that CCL25, the only natural ligand for CCR9, up regulates anti-apoptotic proteins in immature T lymphocytes. Hence, it is plausible that CCR9-mediated cell signals might be involved in OvCa cell survival and inhibition of cisplatin-induced apoptosis. In this study, we investigated the potential role and molecular mechanisms of CCR9-mediated inhibition of cisplatin-induced apoptosis in OvCa cells.
Cell proliferation, vibrant apoptosis, and TUNEL assays were performed with or without cisplatin treatment in presence or absence of CCL25 to determine the role of the CCR9-CCL25 axis in cisplatin resistance. In situ Fast Activated cell-based ELISA (FACE) assays were performed to determine anti-apoptotic signaling molecules responsible for CCL25-CCR9 mediated survival.
Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death. Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3beta and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion.
Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.
顺铂通常用于治疗卵巢癌（OvCa），这主要是由于 OvCa 细胞中的化疗耐药性和上调的抗凋亡机制提供了适度的生存优势。因此，针对 OvCa 细胞中导致顺铂耐药的机制可能会改善治疗效果。我们已经表明卵巢癌细胞表达 CC 趋化因子受体-9（CCR9）。其他人还表明，CCL25 是 CCR9 的唯一天然配体，上调未成熟 T 淋巴细胞中的抗凋亡蛋白。因此，CCR9 介导的细胞信号可能参与 OvCa 细胞的存活和抑制顺铂诱导的细胞凋亡。在这项研究中，我们研究了 CCR9 介导的抑制 OvCa 细胞中顺铂诱导的细胞凋亡的潜在作用和分子机制。
在存在或不存在 CCL25 的情况下，用或不用顺铂处理进行细胞增殖、活力凋亡和 TUNEL 测定，以确定 CCR9-CCL25 轴在顺铂耐药中的作用。进行原位快速激活细胞基于 ELISA（FACE）测定，以确定负责 CCL25-CCR9 介导存活的抗凋亡信号分子。
我们的结果表明 CCR9 和 CCL25 之间的相互作用增加了 OvCa 细胞中的抗凋亡信号级联，从而使细胞免受顺铂诱导的细胞死亡。具体而言，CCL25-CCR9 相互作用以 PI3K 依赖性和 FAK 非依赖性方式介导 Akt 的激活以及 GSK-3β 和 FKHR 的磷酸化。
我们的结果表明 CCR9-CCL25 轴在减少 OvCa 细胞中顺铂诱导的细胞凋亡中起重要作用。
