Docetaxel Down-Regulates the Expression of Androgen Receptor and Prostate-Specific Antigen But Not Prostate-Specific Membrane Antigen in Prostate Cancer Cell Lines: Implications for PSA Surrogacy
Docetaxel Down-Regulates the Expression of Androgen Receptor and Prostate-Specific Antigen But Not Prostate-Specific Membrane Antigen in Prostate Cancer Cell Lines: Implications for PSA Surrogacy
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DOI：
10.1002/pros.21004
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发表时间：
2009-10-01
期刊：
影响因子：
2.8
通讯作者：
Bander, Neil H.
中科院分区：
文献类型：
--
作者：
Kuroda, Kenji;Liu, He;Bander, Neil H.
背景。多西紫杉醇（Docetaxel， DOC）通过促进微管组装和微管捆绑从而抑制有丝分裂而具有强大的抗肿瘤功效。了解到一些抗微管药物会影响前列腺特异性膜抗原（PSMA）表达的极性，以及雄激素消融可以上调PSMA表达，我们试图确定DOC对前列腺癌（PC）细胞系中PSMA表达的影响，作为临床研究的序曲。作为对照，我们还观察了雄激素受体（AR）和前列腺特异性抗原（PSA）的表达。使用LNCaP、CWR22Rv1和MDA-PCa-2b细胞，通过流式细胞术和免疫印迹检测DOC对细胞活力和PSMA、AR和PSA表达的影响。在条件培养基中测定DOC对LNCaP和MDA-PCa-2b细胞PSA水平的影响。通过转染过表达ar的LNCaP和MDA-PCa-2b细胞，研究DOC的作用。PSMA水平不受DOC治疗的影响。出乎意料的是，我们发现DOC在研究的细胞百合中以剂量依赖的方式显著下调AR和PSA。AR过表达部分消除了doc的细胞毒作用。虽然DOC不影响PSMA的表达，但却意外地下调了AR和PSA的表达。doc诱导的AR下调可能是PC中活性的抗肿瘤机制之一。PSA的下调可能解释了在DOC PC试验中报道的PSA应答率（45-50%）明显高于可测量应答率（8-17%），并对DOC试验中得出的PSA替代观察结果有影响。中华医学会医学分会，2009。(C) 2009 Wiley-Liss, Inc。
BACKGROUND. Docetaxel (DOC) has potent anti-tumor efficacy as a result of promoting microtubule assembly and microtubule bundling thereby impairing mitosis. Knowing that some anti-microtubule agents affect the polarity of prostate-specific membrane antigen (PSMA) expression and that androgen ablation can up-regulate PSMA expression, we sought to determine any effect of DOC on PSMA expression in prostate cancer (PC) cell lines as a prelude to a clinical effort. As controls, we also looked at the expression of androgen receptor (AR) and prostate-specific antigen (PSA).METHODS. The effect of DOC on cell viability and PSMA, AR, and PSA expression was examined by flow cytometry and immunoblotting using LNCaP, CWR22Rv1, and MDA-PCa-2b cells. The effect of DOC on PSA levels of LNCaP and MDA-PCa-2b cells was also measured in conditioned media. The effect of DOC was also studied using LNCaP and MDA-PCa-2b cells that were transfected to over-express AR.RESULTS. PSMA levels were not affected by DOC treatment. Unexpectedly, we found DOC significantly down-regulated both AR and PSA in a dose-dependent manner in the cell lilies studied. Over-expression of AR partially abrogated the cytotoxic effects of DOC.CONCLUSIONS. While DOC did not affect PSMA expression, it was unexpectedly found to down-regulate AR and PSA. DOC-induced down-regulation of AR might be one of the anti-tumor mechanisms active in PC. Down-regulation of PSA may account for the significantly higher PSA response rates (45-50%) relative to measurable response rates (8-17%) reported in DOC PC trials and have implications for PSA surrogacy observations derived from DOC trials. Prostate 69: 1579-1585, 2009. (C) 2009 Wiley-Liss, Inc.