Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers
Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers
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DOI：
10.1111/j.1349-7006.2010.01543.x
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发表时间：
2010-06-01
期刊：
影响因子：
5.7
通讯作者：
Wake, Norio
中科院分区：
文献类型：
--
作者：
Ohgami, Tatsuhiro;Kato, Kiyoko;Wake, Norio
MDM 2是p53的直接负调节因子。P53-非依赖性mdm 2-P1和P53-依赖性mdm 2-P2启动子最近已显示具有Sp1结合位点。光神霉素是一种Sp1 DNA结合抑制剂，已在临床上用于治疗高钙血症和某些类型的肿瘤性疾病。在这项研究中，我们研究了光辉霉素的抗癌作用背后的机制。在表达野生型p53的妇科癌细胞中，光神霉素稳定p53并增加p53下游靶基因p53 A和p21的表达，阻止细胞周期，并诱导凋亡。p53信号通路的这种激活是浓度< 50 nm的MTH的特异性作用。光明霉素暂时降低mdm 2-P1和-P2启动子的转录。随后通过激活的p53增加mdm 2-P2启动子活性。上调的MDM 2处于其活性形式，因此减弱了p53活性。虽然光神霉素激活p53并抑制小鼠中人类妇科癌细胞异种移植物的生长，但这伴随着MDM 2的继发性上调。光神霉素和nutlin-3（一种抑制MDM 2-p53相互作用的药物）的联合治疗克服了MDM 2的二次上调，并通过激活p53信号通路诱导细胞凋亡来协同抑制癌细胞生长。这些观察结果提供了一个更好的理解的机制，光神霉素的活性，并建议一个潜在的作用，结合光神霉素和nutlin-3作为妇科癌症的化疗治疗。（Cancer Sci 2010; 101：1387-1395）。
MDM2 is a direct negative regulator of p53. The p53-independent mdm2-P1 and p53-dependent mdm2-P2 promoters have been recently shown to harbor Sp1 binding sites. Mithramycin, an inhibitor of Sp1 DNA binding, has been used clinically to treat hypercalcemia and some types of neoplastic disorders. In this study, we investigated the mechanisms behind the anticancer effect of mithramycin. In gynecologic cancer cells expressing wild-type p53, mithramycin stabilized p53 and increased the expression of the p53 downstream target genes PUMA and p21, arrested the cell cycle, and induced apoptosis. This activation of the p53 signaling pathway was a specific effect of MTH at concentrations < 50 nm. Mithramycin temporally decreased transcription of both the mdm2-P1 and -P2 promoters. This was followed by a subsequent increase of mdm2-P2 promoter activity by activated p53. Up-regulated MDM2 was in its active form, and consequently attenuated p53 activity. Although mithramycin activated p53 and suppressed the growth of human gynecologic cancer cell xenografts in mice, this was accompanied with a secondary up-regulation of MDM2. Combined treatment with mithramycin and nutlin-3, a drug that inhibits MDM2-p53 interaction, overcame a secondary up-regulation of MDM2 and synergistically inhibited cancer cell growth by inducing apoptosis through activation of the p53 signaling pathway. These observations provide a better understanding of the mechanisms of mithramycin activity, and suggest a potential role for combining mithramycin and nutlin-3 as a chemotherapeutic treatment for gynecologic cancers. (Cancer Sci 2010; 101: 1387-1395).