Sensitization of human breast cancer cells to natural killer cell-mediated cytotoxicity by proteasome inhibition
Sensitization of human breast cancer cells to natural killer cell-mediated cytotoxicity by proteasome inhibition
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DOI：
10.1111/j.1365-2249.2008.03818.x
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发表时间：
2009-03-01
影响因子：
4.6
通讯作者：
Murphy, W. J.
中科院分区：
文献类型：
--
作者：
Ames, E.;Hallett, W. H. D.;Murphy, W. J.
蛋白酶体抑制剂Bortezomib具有直接的抗肿瘤作用，并已被证明能使肿瘤细胞对肿瘤坏死因子相关的凋亡诱导配体介导的细胞凋亡敏感。自然杀伤(NK)细胞通过细胞毒颗粒杀伤和细胞凋亡诱导途径，是抗肿瘤反应的有效介导者。因此，我们研究了Bortezomib是否通过人类NK细胞系NK-92敏化人乳腺癌细胞。在短期的体外试验中，Bortezomib不能使MDA-231乳腺癌细胞对NK细胞介导的杀伤敏感。然而，Bortezomib确实使这些细胞上调了与凋亡相关的mRNA以及细胞表面的死亡受体。在一项允许NK细胞充分利用其全部杀伤途径的长期体外肿瘤生长试验中，Bortezomib使三种乳腺癌细胞株对NK细胞介导的杀伤敏感，这导致了比任何一种单独治疗更强的抗肿瘤效果。然后，我们使用了一种异种小鼠模型，在该模型中，CB-17 SCID小鼠被注射了人乳腺癌细胞。该模型显示了NK-92细胞的有效性，但加入硼替佐米并没有进一步提高荷瘤小鼠的存活率，也没有减少肺转移的数量。然而，虽然Bortezomib在体外对NK-92细胞具有高度的细胞毒作用，但体内治疗并没有降低NK-92细胞的功能，这表明通过交替使用Bortezomib的剂量或时机，联合治疗可能会产生更大的疗效。这些数据表明，与单独使用任何一种治疗方法相比，Bortezomib和NK细胞联合治疗人类乳腺癌具有产生更好的抗肿瘤反应的潜力。
The proteasome inhibitor, bortezomib, has direct anti-tumour effects and has been demonstrated to sensitize tumour cells to tumour necrosis factor-related apoptosis-inducing ligand-mediated apoptosis. Natural killer (NK) cells are effective mediators of anti-tumour responses, both through cytotoxic granule killing and apoptosis-inducing pathways. We therefore investigated if bortezomib sensitized human breast cancer cells to killing by the human NK cell line, NK-92. Bortezomib was unable to sensitize MDA-231 breast cancer cells to NK cell-mediated killing in short-term in vitro assays. However, bortezomib did cause these cells to up-regulate apoptosis-related mRNA as well as death receptors on the cell surface. In a long-term in vitro tumour outgrowth assay that allows NK cells to use their full repertoire of killing pathways, bortezomib sensitized three breast cancer cell lines to NK cell-mediated killing, which led to greater anti-tumour effects than either treatment alone. We then used a xenogeneic mouse model in which CB-17 SCID mice were injected with human breast cancer cells. This model displayed the effectiveness of NK-92 cells, but the addition of bortezomib did not increase the survival further or reduce the number of lung metastases in tumour-bearing mice. However, while bortezomib was highly cytotoxic to NK-92 cells in vitro, bortezomib treatment in vivo did not decrease NK-92 function, suggesting that through alternative dosing or timing of bortezomib, greater efficacy may occur from combined therapy. These data demonstrate that combined treatment of human breast cancer with bortezomib and NK cells has the potential to generate superior anti-tumour responses than either therapy alone.