Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL
Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL
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DOI：
10.1038/sj.cgt.7700420
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发表时间：
2002-02-01
影响因子：
6.4
通讯作者：
Norris, JS
中科院分区：
文献类型：
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作者：
Voelkel-Johnson, C;King, DL;Norris, JS
肿瘤坏死因子相关的凋亡诱导配体（TRAIL/Apo2L）已被证明可诱导恶性细胞凋亡而不损害正常细胞。为了确定TRAIL对前列腺细胞的抗肿瘤潜力，我们进行了一项综合研究，包括8种前列腺癌细胞系（CWR22Rv1、Du145、Dupre、JCA-1、LNCaP、PC-3、PPC-1和TsuPr1）和正常前列腺上皮细胞（PrEC）的原代培养。在化疗药物阿霉素存在或不存在的情况下，检测细胞对可溶性TRAIL的敏感性。TRAIL也通过腺病毒载体传递。结果显示，Du145、DuPro、LNCap、TsuPr1和PrEC对100 ng/mL TRAIL耐药。JCA-1和PPC-1对TRAIL的敏感性较弱（杀灭率为20%），PC-3和CWR22Rv1对TRAIL的敏感性最高（杀灭率分别为30%和50%）。10 ng/mL TRAIL联合阿霉素对8个前列腺癌细胞中的7个产生60-80%的细胞毒性。trail介导的细胞凋亡涉及Bid、caspase-3和PARP的裂解，并且需要caspase-8和-9的活性。由腺病毒载体（AdTRAIL-IRES-GFP）传递的全长TRAIL可杀死前列腺癌细胞系和PrEC，而无需阿霉素共治疗。因此，从组织特异性启动子表达转基因将使AdTRAIL-IRES-GFP基因治疗成为可能。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) ha been shown to induce apoptosis in malignant cells without harming normal cells. To determine the antitumor potential of TRAIL against prostate cells, we undertook a comprehensive study that included eight prostate cancer cells lines (CWR22Rv1, Du145, Dupre, JCA-1, LNCaP, PC-3, PPC-1, and TsuPr1) and primary Cultures of normal prostate epithelial cells (PrEC). Cells were tested for susceptibility to soluble TRAIL in the presence or absence of the chemotherapeutic agent doxorubicin. TRAIL was also delivered by an adenoviral vector. Our results reveal that Du145, DuPro, LNCap, TsuPr1, and PrEC were resistant to 100 ng/mL TRAIL. JCA-1 and PPC-1 were slightly sensitive (20% killing) and PC-3 and CWR22Rv1 exhibited the highest sensitivity to TRAIL (30% and 50% killing, respectively). The combination of 10 ng/mL TRAIL with doxorubicin resulted in 60-80% cytotoxicity in seven of eight prostate cancer cells. TRAIL-mediated apoptosis involved cleavage of Bid, caspase-3, and PARP, and required caspase-8 and -9 activity. Full-length TRAIL delivered by an adenoviral vector (AdTRAIL-IRES-GFP) killed prostate cancer cell lines and PrEC without requisite doxorubicin cotreatment. Therefore, expression of the transgene from a tissue-specific promotor would make gene therapy with AdTRAIL-IRES-GFP a possibility.