万珂增强NK 细胞对前列腺癌细胞 杀伤作用的实验研究

Investigation of effect of Bortezomib on natural killer cell–mediated lysis of prostate cancer cells

摘要:

目的 探讨万珂是否能够增强自然杀伤细胞（NK）对前列腺癌细胞的杀伤作用及其作用 机制。方法 以激素依赖性和激素非依赖性2 种前列腺癌细胞株LNCaP 和DU145 为模型，不同浓度（0、10 和20 nmol/L）万珂处理2 种前列腺癌细胞株24 h。采用Annexin-V/PI 法检测细胞凋亡率，流式细胞术检测 人白细胞抗原-ABC（HLA-ABC）蛋白的表达，实时荧光定量聚合酶链反应检测HLA-C mRNA 的表达。 结果 万珂能提高2 种细胞系对NK 细胞介导的杀伤作用的敏感性，而且在激素非依赖性前列腺细胞株 DU145 细胞中表现更明显。万珂能下调DU145 细胞表面HLA- Ⅰ类分子水平。相对DU145 细胞，万珂对激 素依赖性前列腺癌LNCaP 细胞不敏感，万珂处理后LNCaP 细胞中HLA- Ⅰ类分子也没有改变。结论 万珂 通过下调HLA- Ⅰ类分子的表达，增强NK 细胞对前列腺癌的杀伤能力，特别是增强对激素非依赖性前列腺 细胞的杀伤，该作用能提高前列腺癌的治疗水平。

Abstract:

Objective To investigate whether Bortezomib could sensitize NK cells to kill prostate cancer cells and its possible mechanism. Methods In this study, androgen-sensitive prostate cancer cell line LNCaP and androgen-insensitive human prostate cancer cell line DU145 were used as the objects of study, the prostate cancer cells were exposed to various concentrations (0, 10 and 20 nmol/L) of Bortezomib for 24 h. Apoptosis was analyzed using Annexin-V/PI method. The expression of HLA-ABC protein was detected by flow cytometry. qRT-PCR was used to detect the expression of HLA-C mRNA. Results Bortezomib could increase the sensitivity of these two cell lines to NK cell-mediated killing, and DU145 cells were more sensitive to Bortezomib-induced apoptosis. Treatment with Bortezomib down-regulated the HLA-I molecule on the surface of DU145 cells; in contrast, LNCaP cells were not sensitized by this treatment, their HLA-I molecule did not change. Conclusions Bortezomib can enhance the anti-tumor ability of NK cells by down-regulation of the cell-surface expression of HLA-I, especially in androgeninsensitive human prostate cancer cells. This effect can be utilized to sensitize androgen-insensitive human prostate cancer to NK cell-mediated killing and improve current cancer therapies.