Transforming Growth Factor-{beta}-Stimulated Clone-22 Is an Androgen-Regulated Gene That Enhances Apoptosis in Prostate Cancer following Insulin-Like Growth Factor-I Receptor Inhibition.
Transforming Growth Factor-{beta}-Stimulated Clone-22 Is an Androgen-Regulated Gene That Enhances Apoptosis in Prostate Cancer following Insulin-Like Growth Factor-I Receptor Inhibition.
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DOI：
10.1158/1078-0432.ccr-09-0264
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发表时间：
2009-12-15
期刊：
影响因子：
--
通讯作者：
Plymate SR
中科院分区：
文献类型：
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作者：
Sprenger CC;Haugk K;Sun S;Coleman I;Nelson PS;Vessella RL;Ludwig DL;Wu JD;Plymate SR
在雄激素存在的情况下，使用人IGF-IR单抗A12抑制IGF信号在诱导前列腺癌异种移植瘤细胞凋亡方面是最有效的。我们开展了这项研究，以确定在雄激素存在的情况下，A12增加细胞凋亡的机制。将抗去势的人异种移植瘤LuCaP 35V植入完整或去势的SCID小鼠体内，每周给予A12治疗。肿瘤生长6周后，处死动物，取出肿瘤，进行细胞周期分布/细胞凋亡分析和基因芯片分析。在去势的小鼠中，肿瘤在G2期延迟，没有细胞凋亡；相反，完整小鼠的肿瘤发生了细胞凋亡，延迟了G1或G2。与去势小鼠相比，完整小鼠的肿瘤组织中TSC-22显著升高，尤其是在那些细胞凋亡率最高的肿瘤中。为了进一步确定TSC-22的功能，我们将TSC-22的表达载体导入不同的人前列腺癌细胞系。过表达TSC-22的细胞株显示细胞凋亡率增加，G1期延迟。当这些细胞系被放置在SCID小鼠的皮下时，与对照肿瘤相比，形成肿瘤的动物数量减少，肿瘤生长速度降低。这些数据表明，在雄激素存在的情况下抑制IGF-IR在抑制肿瘤生长方面具有增强的作用，部分是通过增加肿瘤抑制基因TSC-22的表达。
Inhibition of IGF signaling using the human IGF-IR monoclonal antibody A12 is most effective at inducing apoptosis in prostate cancer xenografts in the presence of androgen. We undertook this study to determine mechanisms for increased apoptosis by A12 in the presence of androgens. The castrate-resistant human xenograft LuCaP 35V was implanted into intact or castrate SCID mice and treated with A12 weekly. After six weeks of tumor growth animals were sacrificed and tumors removed and analyzed for cell cycle distribution/apoptosis and cDNA arrays were performed. In castrate mice the tumors were delayed in G2 with no apoptosis; in contrast tumors from intact mice underwent apoptosis with either a G1 or G2 delay. TSC-22 was significantly elevated in tumors from the intact mice compared to castrate mice, especially in those tumors with the highest levels of apoptosis. In order to further determine the function of TSC-22, we transfected various human prostate cancer cell lines with a plasmid expressing TSC-22. Cell lines overexpressing TSC-22 demonstrated an increase in apoptosis and a delay in G1. When these cell lines were placed subcutaneously in SCID mice a decreased number of animals formed tumors and the rate of tumor growth was decreased compared to control tumors. These data indicate that IGF-IR inhibition in the presence of androgen has an enhanced effect on decreasing tumor growth, in part, through increased expression of the tumor suppressor gene TSC-22.