Role of Mdm4 in drug sensitivity of breast cancer cells
Role of Mdm4 in drug sensitivity of breast cancer cells
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DOI：
10.1038/onc.2009.522
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发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Jochemsen, A. G.
中科院分区：
文献类型：
--
作者：
Lam, S.;Lodder, K.;Jochemsen, A. G.
p53肿瘤抑制蛋白在人类肿瘤中经常发生突变。据认为，p53通路在其余肿瘤中间接受损，例如通过其重要调节因子Mdm 2和Mdm 4的过表达，使其成为开发抗癌剂的有吸引力的靶点。最近的研究表明，Mdm 4水平决定了肿瘤细胞对抗癌治疗的敏感性。为了研究这种可能性，我们研究了几种含有野生型p53但表达不同Mdm 4水平的乳腺癌细胞系的药物敏感性。我们发现，内源性Mdm 4水平可以影响乳腺癌细胞对抗癌药物的敏感性，但在细胞系依赖性的方式和依赖于一个完整的凋亡反应。此外，用非遗传毒性剂Nutlin-3治疗使细胞对阿霉素敏感，表明通过靶向其调节剂激活p53是降低乳腺癌细胞的细胞活力的有效策略。这些结果证实了Mdm 4在确定化疗剂以p53依赖性方式诱导癌细胞凋亡的功效中的功能，尽管另外的未确定因素也影响药物应答。靶向Mdm 4使肿瘤细胞对化疗药物敏感可能是有效治疗携带野生型p53的肿瘤的策略。Oncogene（2010）29，2415-2426; doi：10.1038/onc.2009.522; 2010年2月8日在线发表
The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53. Oncogene (2010) 29, 2415-2426; doi:10.1038/onc.2009.522; published online 8 February 2010