Inhibition of MDM2 Re-Sensitizes Rapamycin Resistant Renal Cancer Cells via the Activation of p53
Inhibition of MDM2 Re-Sensitizes Rapamycin Resistant Renal Cancer Cells via the Activation of p53
复制标题
通过激活 p53 抑制 MDM2 使雷帕霉素耐药性肾癌细胞重新变得敏感
DOI：
10.1159/000447904
复制
发表时间：
2016-10
影响因子：
--
通讯作者：
Jiang Youhong
中科院分区：
文献类型：
--
作者：
Tian Xin;Dai Shundong;Sun Jing;Jiang Shenyi;Sui Chengguang;Meng F;ong;Li Yan;Fu Liye;Jiang Tao;Wang Yang;Su Jia;Jiang Youhong
背景/目的：雷帕霉素是一种潜在的抗癌药物，它调节mTOR的活性，mTOR是细胞生长和增殖的关键调节因子。然而，几种类型的癌细胞对雷帕霉素的抗增殖作用具有抗性。在这项研究中，我们报告了MDM 2/p53介导的雷帕霉素耐药的人肾癌细胞。方法：台盼蓝拒染法测定细胞活力。mRNA和蛋白质表达的变化分别采用实时PCR和Western印迹法测定。建立异种移植模型以评估雷帕霉素与MDM 2抑制剂组合的体内作用。结果：雷帕霉素处理抑制了MDM 2的表达，外源性MDM 2过表达有助于A498细胞对雷帕霉素产生耐药性。通过建立雷帕霉素抗性细胞系，我们观察到MDM 2在雷帕霉素抗性细胞中比在雷帕霉素敏感细胞中显著上调。重要的是，雷帕霉素抗性细胞表现出响应于雷帕霉素处理的p53在细胞核中的减弱的积累。此外，siMDM 2对MDM 2的抑制通过激活p53使A498细胞对雷帕霉素敏感。在体外和体内模型中，雷帕霉素与MDM 2抑制剂MI-319的组合显示出对雷帕霉素抗性细胞的协同抑制作用。结论：我们的研究报告了一种新的机制，雷帕霉素耐药的人肾癌和抗癌药物的开发提供了一个新的视角。
Background/Aims: Rapamycin is a potential anti-cancer agent, which modulates the activity of mTOR, a key regulator of cell growth and proliferation. However, several types of cancer cells are resistant to the anti-proliferative effects of rapamycin. In this study, we report a MDM2/p53-mediated rapamycin resistance in human renal cancer cells. Methods: Trypan blue exclusion tests were used to determine the cell viability. Changes in mRNA and protein expression were measured using real-time PCR and western blot, respectively. Xenograft models were established to evaluate the in vivo effects of rapamycin combined with a MDM2 inhibitor. Results: Rapamycin treatment suppresses the expression of MDM2 and exogenous overexpression of MDM2 in A498 cells contributes to rapamycin resistance. By establishing a rapamycin resistant cell line, we observed that MDM2 was significantly upregulated in rapamycin resistant cells than that in rapamycin sensitive cells. Importantly, the rapamycin resistant cells demonstrated attenuated accumulation of p53 in the nucleus in response to rapamycin treatment. Moreover, the inhibition of MDM2 by siMDM2 sensitizes A498 cells to rapamycin through the activation of p53. In both in vitro and in vivo models, the combination of rapamycin with the MDM2 inhibitor, MI-319, demonstrated a synergistic inhibitory effect on rapamycin resistant cells. Conclusion: Our study reports a novel mechanism for rapamycin resistance in human renal cancer and provides a new perspective for the development of anti-cancer drugs.
登录
查看更多内容
影响因子：
8
作者：
H. Beamish;R. Williams;Philip C. Chen;K. Khanna;K. Hobson;D. Watters;Yosef Shiloh;M. Lavin
通讯作者：
H. Beamish;R. Williams;Philip C. Chen;K. Khanna;K. Hobson;D. Watters;Yosef Shiloh;M. Lavin
影响因子：
8.4
作者：
Azmi, Asfar S.;Aboukameel, Amro;Banerjee, Sanjeev;Wang, Zhiwei;Mohammad, Momin;Wu, Jack;Wang, Shaomeng;Yang, Dajun;Philip, Philip A.;Sarkar, Fazlul H.;Mohammad, Ramzi M.
通讯作者：
Mohammad, Ramzi M.
雷帕霉素抑制IGF-1介导的MDM2上调，并使癌细胞对化学疗法敏感。
影响因子：
3.7
作者：
Du W;Yi Y;Zhang H;Bergholz J;Wu J;Ying H;Zhang Y;Xiao ZX
通讯作者：
Xiao ZX
影响因子：
11.4
作者：
Shima, H;Pende, M;Kozma, SC
通讯作者：
Kozma, SC
影响因子：
5.3
作者：
P. Dennis;Nicholas Pullen;S. Kozma;George Thomas
通讯作者：
P. Dennis;Nicholas Pullen;S. Kozma;George Thomas