Luu Yvonne, Bush Jason, Cheung K-John, Li Gang
Division of Dermatology, Department of Medicine, Vancouver Hospital, Health Sciences Centre, University of British Columbia, Canada.
Exp Cell Res. 2002 Jun 10;276(2):214-22. doi: 10.1006/excr.2002.5526.
p53 is considered the guardian of the genome and has a number of biological functions, including cell cycle arrest, DNA repair, and apoptosis. In a recent study by Foster and colleagues, the pharmacological compound CP-31398 was found to stabilize wild-type p53 to enhance its transcriptional activity and inhibit tumor growth in mice. We hypothesize that CP-31398 induces apoptosis by stabilizing the p53 protein and activating the mitochondrial-mediated pathway. Using the wild-type p53 HCT116+/+ and the p53-deficient HCT116-/- colon carcinoma cell lines, we demonstrate here that CP-31398 induces apoptosis in a dose-, time-, and p53-dependent manner. CP-31398 dramatically elevated p53 and p21(Waf1) protein levels in HCT116+/+, while a smaller p53-independent p21(Waf1) induction by CP-31398 in HCT116-/- cells was also observed. Moreover, we also found that CP-31398 increased Bax expression, altered mitochondrial membrane potential causing the release of cytochrome c, and induced the cleavage of caspases-9 and -3. Taken together, our results indicate that CP-31398 induces p53-dependent apoptosis by activating the Bax/mitochondrial/caspase-9 pathway. Elucidating the mechanism by which CP-31398 induces cell death may establish it as an anticancer agent.
p53被认为是基因组的守护者，具有多种生物学功能，包括细胞周期阻滞、DNA修复和细胞凋亡。在福斯特及其同事最近的一项研究中，发现药理化合物CP - 31398可稳定野生型p53，以增强其转录活性并抑制小鼠肿瘤生长。我们推测CP - 31398通过稳定p53蛋白并激活线粒体介导的途径诱导细胞凋亡。使用野生型p53的HCT116+/+和p53缺陷型的HCT116-/-结肠癌细胞系，我们在此证明CP - 31398以剂量、时间和p53依赖性方式诱导细胞凋亡。CP - 31398显著提高了HCT116+/+中p53和p21（Waf1）蛋白水平，同时在HCT116-/-细胞中也观察到CP - 31398对p21（Waf1）有较小的不依赖p53的诱导作用。此外，我们还发现CP - 31398增加了Bax表达，改变了线粒体膜电位导致细胞色素c释放，并诱导了caspases - 9和 - 3的裂解。综上所述，我们的结果表明CP - 31398通过激活Bax/线粒体/caspase - 9途径诱导p53依赖性细胞凋亡。阐明CP - 31398诱导细胞死亡的机制可能会将其确立为一种抗癌药物。
