...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Cellular Physiology >Inorganic phosphate enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin via a p53-dependent pathway
【24h】

Inorganic phosphate enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin via a p53-dependent pathway

机译：无机磷酸盐提高灵敏度的人类骨肉瘤U2OS细胞通过一个阿霉素p53-dependent通路

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. The clinical outcome for osteosarcoma remains discouraging despite aggressive surgery and intensive radiotherapy and chemotherapy regimens. Thus, novel therapeutic approaches are needed. Previously, we have shown that inorganic phosphate (Pi) inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. In this study, we investigated whether Pi could affect chemosensitivity of osteosarcoma cells and the underlying molecular mechanisms. Here, we report that Pi inhibits proliferation of p53-wild type U2OS cells (and not of p53-null Saos and p53-mutant MG63 cells) by slowing-down cell cycle progression, without apoptosis occurrence. Interestingly, we found that Pi strongly enhances doxorubicin-induced cytotoxicity in U2OS, and not in Saos and MG63 cells, by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation, and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was accompanied by an increase of p53 protein levels and of p53 target genes mdm2, p21 and Bax, and was significantly reduced by the p53 inhibitor pifithrine-alpha. Moreover, the doxorubicin-induced cytotoxicity was associated with ERK1/2 pathway inhibition in response to Pi. Altogether, our data enforce the evidence of Pi as a novel signaling molecule capable of inhibiting ERK pathway and inducing sensitization to doxorubicin of osteosarcoma cells by p53-dependent apoptosis, implying that targeting Pi levels might represent a rational strategy for improving osteosarcoma therapy.
机译：骨肉瘤是最常见的恶性原发性骨肿瘤在儿童和青少年。骨肉瘤的临床结果沮丧尽管积极的手术密集的放疗和化疗方案。因此,新颖的治疗方法是必要的。以前,我们已经表明,无机磷酸(Pi)抑制增殖和人类骨肉瘤U2OS细胞的侵犯识别腺苷酸环化酶,beta3整合素,Rap1, ERK1/2蛋白质的表达和函数贴切地响应的影响π。可能会影响骨肉瘤的化学敏感性细胞和潜在的分子机制。在这里,我们报告,π抑制扩散p53-wild U2OS细胞(而不是p53-null类型巴西和p53突变MG63细胞)的减速细胞周期进展,没有细胞凋亡发生。大力提高doxorubicin-induced在U2OS细胞毒性,不是在巴西和MG63细胞,通过细胞凋亡归纳,揭示了sub-G1人口的显著增加,bcl - 2downregulation caspase-3激活,PARP分裂combination-induced细胞毒性是陪同通过增加p53蛋白水平和p53的目标基因mdm2、p21和伯灵顿,由p53抑制剂显著降低pifithrine-alpha。doxorubicin-induced细胞毒性有关反应到πERK1/2通路抑制。总之,我们的数据执行π的证据小说作为一种信号分子的能力抑制ERK通路,诱导敏感骨肉瘤细胞的阿霉素p53-dependent细胞凋亡,这意味着目标π水平可能代表一个合理的策略提高骨肉瘤治疗。

著录项

相似文献

  • 外文文献
  • 中文文献
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号