Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53.
Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53.
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DOI：
10.1016/j.ygyno.2012.11.004
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发表时间：
2013-03
影响因子：
4.7
通讯作者：
Leslie KK
中科院分区：
文献类型：
--
作者：
Meng X;Laidler LL;Kosmacek EA;Yang S;Xiong Z;Zhu D;Wang X;Dai D;Zhang Y;Wang X;Brachova P;Albitar L;Liu D;Ianzini F;Mackey MA;Leslie KK
带有无功能p53的子宫内膜肿瘤，如浆液性子宫内膜癌，是侵袭性的恶性肿瘤，预后不佳，但它们有一个致命的弱点：由于p53功能的丧失，这些肿瘤可能对取消G2/M检查点的治疗敏感。我们的目标是利用这一弱点通过两种策略来诱导有丝分裂细胞死亡：(1)EGFR抑制剂吉非替尼联合紫杉醇阻止细胞有丝分裂，或(2)Polo-like kinase1(PLK1)抑制剂BI2536阻断PLK1活性。我们检测了联合应用吉非替尼和紫杉醇或PLK1抑制剂对带有突变型p53的子宫内膜癌细胞G2/M检查点控制器的表达、细胞活力和细胞周期进展的影响。在缺乏正常P53活性的细胞中，每种处理都激活了CDC25C和失活了Wee1，进而激活了CDC2，并将细胞迅速通过G2/M检查点，进入有丝分裂。活细胞成像显示不可逆转的有丝分裂停滞和最终的细胞死亡。紫杉醇和吉非替尼的联合治疗具有高度的协同作用，导致紫杉醇的IC50降低了10倍，从单一药物的14 NM降至Gefitinib存在时的1.3 NM。然而，BI2536单独在低浓度(5 NM)时是最有效的治疗方法，并导致大量有丝分裂细胞死亡。在p53缺失细胞的异种移植小鼠模型中，低剂量BI2536显著抑制肿瘤生长。这些发现揭示了诱导有丝分裂细胞死亡是治疗缺乏功能性P53的子宫内膜肿瘤的一种策略。
Endometrial tumors with non-functional p53, such as serous uterine endometrial carcinomas, are aggressive malignancies with a poor outcome, yet they have an Achilles’ heel: due to loss of p53 function, these tumors may be sensitive to treatments which abrogate the G2/M checkpoint. Our objective was to exploit this weakness to induce mitotic cell death using two strategies: (1) EGFR inhibitor gefitinib combined with paclitaxel to arrest cells at mitosis, or (2) BI2536, an inhibitor of polo-like kinase 1 (PLK1), to block PLK1 activity. We examined the impact of combining gefitinib and paclitaxel or PLK1 inhibitor on expression of G2/M checkpoint controllers, cell viability, and cell cycle progression in endometrial cancer cells with mutant p53. In cells lacking normal p53 activity, each treatment activated CDC25C and inactivated Wee1, which in turn activated cdc2 and sent cells rapidly through the G2/M checkpoint and into mitosis. Live cell imaging demonstrated irreversible mitotic arrest and eventual cell death. Combinatorial therapy with paclitaxel and gefitinib was highly synergistic and resulted in a 10-fold reduction in the IC50 for paclitaxel, from 14 nM as a single agent to 1.3 nM in the presence of gefitinib. However, BI2536 alone at low concentrations (5 nM) was the most effective treatment and resulted in massive mitotic cell death. In a xenograft mouse model with p53-deficient cells, low dose BI2536 significantly inhibited tumor growth. These findings reveal induction of mitotic cell death as a therapeutic strategy for endometrial tumors lacking functional p53.
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影响因子：
5.8
作者：
Ianzini F;Bertoldo A;Kosmacek EA;Phillips SL;Mackey MA
通讯作者：
Mackey MA
影响因子：
11.2
作者：
Dai, DH;Holmes, AM;Leslie, KK
通讯作者：
Leslie, KK
影响因子：
11.2
作者：
Ianzini F;Kosmacek EA;Nelson ES;Napoli E;Erenpreisa J;Kalejs M;Mackey MA
通讯作者：
Mackey MA
影响因子：
2
作者：
Davis, Paul J.;Kosmacek, Elizabeth A.;Mackey, Michael A.
通讯作者：
Mackey, Michael A.
影响因子：
45.3
作者：
Fleming, GF;Brurietto, VL;Burks, RT
通讯作者：
Burks, RT