Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma.
Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma.
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DOI：
10.1158/1535-7163.mct-12-0903
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发表时间：
2013-05
影响因子：
5.7
通讯作者：
Raychaudhuri P
中科院分区：
文献类型：
--
作者：
Wang Z;Zheng Y;Park HJ;Li J;Carr JR;Chen YJ;Kiefer MM;Kopanja D;Bagchi S;Tyner AL;Raychaudhuri P
叉头盒转录因子FOXM1被认为是一个有前途的肿瘤治疗靶点。然而，FOXM1在携带p53突变的肿瘤中的意义尚不清楚，这是非常常见的。在这项研究中，我们研究了使用基因消融以及使用FOXM1的肽抑制剂的FoxM1靶向在自发性p53缺失肿瘤中的功效。我们发现，FoxM1的条件性缺失抑制p53无效的胸腺淋巴瘤和肉瘤细胞的生长。此外，FoxM 1的缺失会诱导p53缺失肿瘤的细胞凋亡，同时伴有FOXM 1靶基因Survivin和Bmi 1的表达减少。一种通过靶向细胞核抑制FOXM1活性的ARF衍生肽也诱导p53无效肉瘤和淋巴瘤中的细胞凋亡，从而强烈抑制其转移性定植。总之，我们的观察结果表明，FOXM1对p53无效淋巴瘤和肉瘤的生存和生长至关重要，并提供了FOXM1是携带p53功能缺失突变的肉瘤和淋巴瘤的有效治疗靶点的原理证明。
The forkhead box transcription factor FOXM1 is considered to be a promising target for cancer therapy. However, the significance of FOXM1 in tumors harboring mutation in p53, which is very common, is unclear. In this study, we investigated the efficacy of FoxM1-targeting in spontaneous p53-null tumors using genetic ablation as well as using a peptide-inhibitor of FOXM1. We show that conditional deletion of FoxM1 inhibits growth of the p53 null thymic lymphoma and sarcoma cells. In addition, deletion of FoxM1 induces apoptotic cell death of the p53 null tumors, accompanied by reduced expression of the FOXM1 target genes Survivin and Bmi1. An ARF-derived peptide that inhibits the activity of FOXM1, by targeting it to the nucleolus, also induces apoptosis in the p53 null sarcoma and lymphoma, leading to a strong inhibition of their metastatic colonization. Together, our observations suggest that FOXM1 is critical for survival and growth of the p53-null lymphoma and sarcoma, and provide proof-of-principle that FOXM1 is an effective therapeutic target for sarcoma and lymphoma carrying loss of function mutation in p53.