Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Oncogene. 2010 Apr 22;29(16):2415-26. doi: 10.1038/onc.2009.522. Epub 2010 Feb 8.
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.
p53 肿瘤抑制蛋白在人类肿瘤中经常发生突变。人们认为，p53 途径在其余肿瘤中会间接受损，例如其重要调节因子 Mdm2 和 Mdm4 的过度表达，这使其成为开发抗癌药物的有吸引力的靶点。最近的研究表明，Mdm4 水平决定了肿瘤细胞对癌症治疗的敏感性。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 Mdm4 水平的乳腺癌细胞系的药物敏感性。我们表明，内源性 Mdm4 水平可以影响乳腺癌细胞对抗癌药物的敏感性，但以细胞系依赖性的方式，并取决于完整的凋亡反应。此外，用非遗传毒性药物 Nutlin-3 处理可使细胞对阿霉素敏感，表明通过靶向其调节因子激活 p53 是降低乳腺癌细胞活力的有效策略。这些结果证实了 Mdm4 在以 p53 依赖的方式确定化疗药物诱导癌细胞凋亡的功效中的作用，尽管还有其他未确定的因素也会影响药物反应。针对 Mdm4 使肿瘤细胞对化疗药物敏感可能是一种有效治疗携带野生型 p53 的肿瘤的策略。
