Raloxifene inhibits growth of RT4 urothelial carcinoma cells via estrogen receptor-dependent induction of apoptosis and inhibition of proliferation.
Raloxifene inhibits growth of RT4 urothelial carcinoma cells via estrogen receptor-dependent induction of apoptosis and inhibition of proliferation.
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DOI：
10.1007/s12672-012-0123-9
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发表时间：
2013-02
影响因子：
3
通讯作者：
Smith CL
中科院分区：
文献类型：
--
作者：
Hoffman KL;Lerner SP;Smith CL
膀胱癌是美国第五常见的癌症类型，每年诊断出超过70，000例新病例。治疗通常涉及侵入性手术治疗，因为单独的化疗通常无效且与高复发率相关。在高达75%的泌尿系肿瘤中鉴定出雌激素受体-β（ERβ），这提出了一个问题，即这种受体是否可以靶向有效治疗膀胱癌。在这项研究中，一组代表各种疾病阶段和等级的五种膀胱癌细胞系用抗雌激素4-羟基他莫昔芬、雷洛昔芬或纯拮抗剂ICI 182，780处理。所有细胞系均为ERβ阳性，只有少数细胞系表达ERα。值得注意的是，除了TCC 12细胞系之外，所有细胞系的生长都被至少两种抗雌激素抑制20-100%。使用RT 4细胞，我们证明雷洛昔芬的生长抑制是ER依赖性的，ERα或ERβ可以介导这种反应。caspase-3及其效应物PARP的激活表明雷洛昔芬诱导的生长抑制部分是细胞凋亡增加的结果;这种PARP裂解是ER依赖性的。此外，细胞周期基因表达的变化表明细胞增殖也受到影响。具体而言，雷洛昔芬治疗可能通过下调SKP 2导致p27蛋白稳定。细胞周期负调控因子B细胞易位基因2（BTG 2）的表达也增加，而细胞周期蛋白D1的转录减少。这些结果表明，抗雌激素可能是有用的目标，在治疗膀胱癌的ER和抑制生长通过多种机制。
Bladder cancer is the fifth most common type of cancer in the United States, with over 70,000 new cases diagnosed each year. Treatment often involves invasive surgical therapies, as chemotherapy alone is often ineffective and associated with high recurrence rates. Identification of estrogen receptor-β (ERβ) in up to 75% of urinary tumors raises the question of whether this receptor could be targeted to effectively treat bladder cancer. In this study, a panel of five bladder cancer cell lines representing a variety of disease stage and grades were treated with the antiestrogens 4-hydroxytamoxifen, raloxifene or the pure antagonist ICI 182,780. All cell lines were ERβ-positive, while only a few expressed ERα. Notably, all but the TCCSUP cell line were growth inhibited 20-100% by at least two antiestrogens. Using RT4 cells, we demonstrate that growth inhibition by raloxifene is ER-dependent and either ERα or ERβ can mediate this response. Activation of caspase-3 and its effector PARP demonstrate that raloxifene-induced growth inhibition is in part the result of increased apoptosis; this PARP cleavage was ER-dependent. Moreover, changes in the expression of cell cycle genes indicate that cell proliferation is also affected. Specifically, raloxifene treatment results in the stabilization of p27 protein, likely via the downregulation of SKP2. Expression of the negative cell cycle regulator B-cell Translocation Gene 2 (BTG2) is also increased, while cyclin D1 transcription is reduced. These results indicate that antiestrogens may be useful targets in the treatment of bladder cancer by targeting ER and inhibiting growth via multiple mechanisms.
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影响因子：
4.8
作者：
Gundimeda, U;Chen, ZH;Gopalakrishna, R
通讯作者：
Gopalakrishna, R
影响因子：
2.6
作者：
Kontos, Stylianos;Kominea, Athina;Sotiropoulou-Bonikou, Georgia
通讯作者：
Sotiropoulou-Bonikou, Georgia
影响因子：
23.4
作者：
Maruyama, S;Fujimoto, N;Usui, T
通讯作者：
Usui, T
影响因子：
4.8
作者：
Hall, JM;McDonnell, DP
通讯作者：
McDonnell, DP
影响因子：
21.3
作者：
Carrano, AC;Eytan, E;Pagano, M
通讯作者：
Pagano, M