Department of Pathology, Wayne State University, Detroit MI, USA.
Haematologica. 2013 Jul;98(7):1098-106. doi: 10.3324/haematol.2012.074781. Epub 2013 Feb 12.
The nuclear export protein chromosome maintenance region 1, found to be elevated in non-Hodgkin's lymphomas, controls localization of critical tumor suppressor proteins. Nuclear localization of tumor suppressor proteins is necessary for their cell surveillance function. However, their nuclear exclusion by chromosome maintenance region 1 renders them ineffective making this nuclear transporter an attractive therapeutic target. We have identified selective inhibitors of nuclear export that lock tumor suppressor proteins in the cell nucleus leading to apoptosis of lymphoid but not normal cells. Our inhibitors induce tumor suppressor protein nuclear retention-dependent growth inhibition and apoptosis in a panel of non-Hodgkin's lymphoma cell lines. Western blot of nuclear protein fraction and confocal microscopy analysis demonstrated retention of major tumor suppressor proteins in the cell nucleus. Co-immunoprecipitation studies showed disruption of the tumor suppressor protein-chromosome maintenance region 1 interaction. Small inhibitor RNA knockdown of two major tumor suppressor proteins, p53 in wild-type protein-53 and protein 73 in mutant-protein-53, abrogated inhibitor activity. Oral administration of related inhibitor at 75 and 150 mg/kg resulted in 65 and 70% tumor reduction, respectively and subcutaneous injections of inhibitor (25 and 75 mg/kg) resulted in 70 and 74% suppression of non-Hodgkin's lymphoma tumor growth with no toxicity; residual tumors showed activation of the protein 73 pathway. Our study verifies chromosome maintenance region 1 as a therapeutic target in non-Hodgkin's lymphoma, indicating that this nuclear export protein warrants further clinical investigations.
核输出蛋白染色体维持区 1 在非霍奇金淋巴瘤中升高，控制关键肿瘤抑制蛋白的定位。肿瘤抑制蛋白的核定位对于其细胞监视功能是必要的。然而，它们被染色体维持区 1 排斥出核，使其无效，这使得这种核转运蛋白成为一个有吸引力的治疗靶点。我们已经确定了选择性的核输出抑制剂，这些抑制剂将肿瘤抑制蛋白锁定在细胞核内，导致淋巴细胞而非正常细胞凋亡。我们的抑制剂在一系列非霍奇金淋巴瘤细胞系中诱导肿瘤抑制蛋白核保留依赖性生长抑制和凋亡。核蛋白部分的 Western blot 和共聚焦显微镜分析显示主要肿瘤抑制蛋白保留在细胞核内。共免疫沉淀研究表明肿瘤抑制蛋白-染色体维持区 1 相互作用被破坏。两种主要肿瘤抑制蛋白 p53 在野生型蛋白-53 和蛋白 73 在突变型蛋白-53 中的小抑制剂 RNA 敲低，消除了抑制剂的活性。口服给予相关抑制剂 75 和 150 mg/kg，分别导致 65%和 70%的肿瘤减少，皮下注射抑制剂（25 和 75 mg/kg）导致 70%和 74%的非霍奇金淋巴瘤肿瘤生长抑制，无毒性；残留肿瘤显示蛋白 73 途径的激活。我们的研究验证了染色体维持区 1 作为非霍奇金淋巴瘤的治疗靶点，表明这种核输出蛋白值得进一步的临床研究。
