Kazi Aslamuzzaman, Carie Adam, Blaskovich Michelle A, Bucher Cynthia, Thai Van, Moulder Stacy, Peng Hairuo, Carrico Dora, Pusateri Erin, Pledger Warren J, Berndt Norbert, Hamilton Andrew, Sebti Saïd M
Drug Discovery Program, Moffitt Cancer Center, Tampa, FL 33612, USA.
Mol Cell Biol. 2009 Apr;29(8):2254-63. doi: 10.1128/MCB.01029-08. Epub 2009 Feb 9.
We describe the design of a potent and selective peptidomimetic inhibitor of geranylgeranyltransferase I (GGTI), GGTI-2418, and its methyl ester GGTI-2417, which increases the levels of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) and induces breast tumor regression in vivo. Experiments with p27(Kip1) small interfering RNA in breast cancer cells and p27(Kip1) null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27(Kip1). GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27(Kip1) at Thr187 and accumulates p27(Kip1) in the nucleus. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. Furthermore, in ErbB2 transgenic mice, GGTI-2418 increases p27(Kip1) and induces significant regression of breast tumors. We conclude that GGTIs' antitumor activity is, at least in part, due to inhibiting Cdk2-dependent p27(Kip1) phosphorylation at Thr187 and accumulating nuclear p27(Kip1). Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27(Kip1) levels.
我们描述了一种高效且具选择性的香叶基香叶基转移酶I（GGTI）肽模拟物抑制剂GGTI-2418及其甲酯GGTI-2417的设计，它们可提高细胞周期蛋白依赖性激酶（Cdk）抑制剂p27（Kip1）的水平，并在体内诱导乳腺肿瘤消退。在乳腺癌细胞中使用p27（Kip1）小干扰RNA以及在p27（Kip1）缺失的小鼠胚胎成纤维细胞中进行的实验表明，GGTI-2417诱导细胞死亡的能力需要p27（Kip1）。GGTI-2417抑制Cdk2介导的p27（Kip1）在苏氨酸187位点的磷酸化，并使p27（Kip1）在细胞核中积累。在裸鼠异种移植模型中，GGTI-2418抑制人乳腺肿瘤的生长。此外，在ErbB2转基因小鼠中，GGTI-2418增加p27（Kip1）并诱导乳腺肿瘤显著消退。我们得出结论，GGTIs的抗肿瘤活性至少部分归因于抑制Cdk2依赖性的p27（Kip1）在苏氨酸187位点的磷酸化以及细胞核中p27（Kip1）的积累。因此，GGTI治疗可能改善核p27（Kip1）水平低的乳腺癌患者的不良预后。
