James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Int J Cancer. 2010 Nov 1;127(9):2020-30. doi: 10.1002/ijc.25219.
Despite recent advances in treatment and management of prostate cancer (PCa), it remains the second leading cause of cancer-related deaths among men in the US. Chemotherapy is one of the treatment alternatives for hormone refractory metastatic PCa. However, current chemotherapeutic regimens provide palliative benefit but relatively modest survival advantage primarily due to chemo-resistance and upregulated antiapoptotic machineries in PCa cells. Therefore, blocking the mechanisms responsible for suppression of apoptosis might improve current chemotherapeutic regimens. In this study, we show that CC chemokine receptor-9 (CCR9) and its natural ligand CCL25 interaction upregulates antiapoptotic proteins (i.e., PI3K, AKT, ERK1/2 and GSK-3beta) and downregulate activation of caspase-3 in PCa cells. Significant downregulation of these CCR9-mediated antiapoptotic proteins in the presence of a PI3K inhibitor (wortmannin), further suggests that the antiapoptotic action of CCR9 is primarily regulated through PI3K. Furthermore, the cytotoxic effect of etoposide was significantly inhibited in the presence of CCL25, and this inhibitory effect of CCL25 was abrogated when CCR9-CCL25 interaction was blocked using anti-CCR9 monoclonal antibodies. In conformation to these in vitro studies, significant reduction in tumor burden was found in mice receiving CCL25 neutralizing antibodies and etoposide together as compared to both as a single agent. These results suggest that the CCR9-CCL25 axis mediates PI3K/AKT-dependent antiapoptotic signals in PCa cells and could be a possible reason for low apoptosis and modest chemotherapeutic response. Therefore, targeting CCR9-CCL25 axis with cytotoxic agents may provide better therapeutic outcomes than using cytotoxic agents alone.
尽管前列腺癌（PCa）的治疗和管理取得了一些进展，但它仍然是美国男性癌症相关死亡的第二大原因。化疗是激素难治性转移性 PCa 的治疗选择之一。然而，目前的化疗方案主要提供姑息性益处，而生存优势相对较小，这主要是由于 PCa 细胞中的化疗耐药性和上调的抗凋亡机制。因此，阻断导致细胞凋亡抑制的机制可能会改善目前的化疗方案。在这项研究中，我们表明 C 型趋化因子受体 9（CCR9）及其天然配体 CCL25 的相互作用上调了抗凋亡蛋白（即 PI3K、AKT、ERK1/2 和 GSK-3β），并下调了 PCa 细胞中 caspase-3 的激活。在存在 PI3K 抑制剂（wortmannin）的情况下，这些 CCR9 介导的抗凋亡蛋白的显著下调进一步表明 CCR9 的抗凋亡作用主要通过 PI3K 调节。此外，在 CCL25 存在的情况下，依托泊苷的细胞毒性作用显著受到抑制，而当使用抗 CCR9 单克隆抗体阻断 CCR9-CCL25 相互作用时，这种 CCL25 的抑制作用被消除。与这些体外研究一致，与单独使用这两种药物相比，接受 CCL25 中和抗体和依托泊苷联合治疗的小鼠肿瘤负担明显减轻。这些结果表明，CCR9-CCL25 轴在 PCa 细胞中介导 PI3K/AKT 依赖性抗凋亡信号，这可能是凋亡率低和化疗反应适度的原因之一。因此，用细胞毒性药物靶向 CCR9-CCL25 轴可能比单独使用细胞毒性药物提供更好的治疗效果。
