通过招募到DCAF15,通过诱导RBM39降解来合抗癌胺
Ting Han1, Maria Goralski2, Nicholas Gaskill2
1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science (New York, N.Y.)
|March 18, 2017
概括
印苏拉姆抗癌药物向RNA结合动机蛋白39 (RBM39),通过CUL4- DCAF15复合体降解,影响mRNA前拼接. DCAF15表达水平与癌细胞对印苏拉姆和相关的SPLAM药物的敏感性相关.
科学领域:
- 癌症学
- 分子生物学
- 药理学
背景情况:
- 印苏拉姆是一种具有选择性抗癌活性的硫胺.
- 在此之前,indisulam的确切作用机制和选择性基础是未知的.
研究的目的:
- 阐明印苏拉姆抗癌活性和选择性的分子机制.
- 确定潜在的生物标志物来预测患者对印苏拉姆和相关药物的反应.
主要方法:
- 通过生物化学测试,研究了印苏拉姆与细胞蛋白的相互作用.
- 分析了印苏拉姆对RBM39无化和降解的影响.
- 评估了印苏拉姆对癌细胞线前mRNA拼接的影响.
- 与各种癌细胞表达水平相关的药物敏感性.
主要成果:
- 印苏拉姆促进了RNA结合基因蛋白39 (RBM39) 与CUL4- DCAF15 E3无酸结合酶的结合.
- 这种招募导致RBM39多化和蛋白质体降解,导致异常的mRNA前拼接.
- 阻止RBM39的突变会对印地苏拉姆产生抗药性.
- 在造血和淋巴癌细胞系中对indisulam的敏感性与DCAF15表达相关.
结论:
- 通过CUL4- DCAF15复合体向RBM39, 破坏mRNA前拼接.
- DCAF15表达是SPLAM (拼接抑制剂硫胺) 的潜在预测生物标志物,包括indisulam,tasisulam和chloroquinoxaline硫胺.
- 这一发现为临床试验和患者选择基于SPLAM的治疗提供了指导的基础.
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