MDM2 antagonist Nutlin-3a protects wild-type p53 cancer cells from paclitaxel  

作　　者：SHEN HongChang DONG Wei GAO DongWei WANG GuangHui MA GuoYuan LIU Qi DU JiaJun 

机构地区：[1]Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan 250021, China

出　　处：《Chinese Science Bulletin》2012年第9期1007-1012,共6页

基　　金：supported by the National High-Tech Research and Development Program of China (2007AA021802);the Provincial Natural Science Foundation of Shandong (ZR2010HM067 and ZR2011HM077)

摘　　要：The p53 pathway has an important role in cell cycle arrest and apoptosis.Downregulated levels of p53 have been shown to increase resistance to the cytotoxic effects of chemotherapy or radiotherapy.MDM2(murine double minute 2) is able to bind p53 and modulate its transcriptional activity and stability.We studied the effect of Nutlin-3a,an MDM2 antagonist,on the response of non-small cell lung cancer cell lines,A549(p53+/+) and H1299(p53-/-),to paclitaxel(Taxol).A549 cells treated with Nutlin-3a plus paclitaxel showed a significant increase in MDM2 and wild-type p53 protein,a marked increase in the number of cells in the G0-G1 and G2-M phases,and a significant decrease in the percentage of cells in the S phase.The percentage of apoptotic A549 cells treated with 10 μmol/L Nutlin-3a plus 10 nmol/L paclitaxel was significantly lower than those treated with paclitaxel alone,and was also lower than that observed in H1299 cells.MTT assays demonstrated that Nutlin-3a plus paclitaxel also significantly reduced the sensitivity of A549 cells to paclitaxel compared with that of H1299 cells.In conclusion,Nutlin-3a mediates the cytotoxic effect of paclitaxel depending on p53 status.It may also protect wild-type p53 cells from mitotic chemotherapeutics.The p53 pathway has an important role in cell cycle arrest and apoptosis. Downregulated levels of p53 have been shown to in- crease resistance to the cytotoxic effects of chemotherapy or radiotherapy. MDM2 （murine double minute 2） is able to bind p53 and modulate its transcriptional activity and stability. We studied the effect of Nutlin-3a, an MDM2 antagonist, on the response of non-small cell lung cancer cell lines, A549 （p53＋/＋） and H1299 （p53-/-）, to paclitaxel （Taxol）. A549 cells treated with Nutlin-3a plus paclitaxel showed a significant increase in MDM2 and wild-type p53 protein, a marked increase in the number of cells in the G0-G1 and G2-M phases, and a significant decrease in the percentage of cells in the S phase. The percentage of apoptotic A549 cells treated with 10 ~tmol/L Nutlin-3a plus 10 nmol/L paclitaxel was significantly lower than those treated with paclitaxel alone, and was also lower than that observed in H1299 cells. MTT assays demonstrated that Nutlin-3a plus paclitaxel also significantly reduced the sensitivity of A549 cells to paclitaxel compared with that of H1299 cells. In conclusion, Nutlin-3a mediates the cyto- toxic effect of paclitaxel depending on p53 status. It may also protect wild-type p53 cells from mitotic chemotherapeutics.

关 键 词：p53蛋白 MDM2 紫杉醇 癌细胞 野生型 拮抗剂 保护 A549细胞 

分 类 号：Q71[生物学—分子生物学] Q691.5