Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis
Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis
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DOI：
10.1038/sj.onc.1207171
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发表时间：
2004-01-22
期刊：
影响因子：
8
通讯作者：
Cheng, JQ
中科院分区：
文献类型：
--
作者：
Dan, HC;Jiang, K;Cheng, JQ
香叶基香叶基转移酶I抑制剂（GGTI）代表一类新的抗癌药物。然而，GGTI抑制肿瘤细胞生长的机制仍不清楚。在这里，我们证明，GGTI-298和GGTI-2166诱导细胞凋亡的顺铂敏感和耐药的人卵巢上皮癌细胞通过抑制PI 3 K/AKT和生存素途径。GGTI-298或GGTI-2166治疗后，PI 3 K和AKT的激酶水平降低，生存素表达显著降低。组成型活性AKT 2和/或生存素的异位表达可显着拯救人类癌细胞免受GGTI-298诱导的细胞凋亡。以前的研究表明，Akt介导生长因子诱导的生存素，而p53抑制生存素的表达。然而，组成性活跃的AKT 2未能挽救GGTI对生存素的下调。此外，GGTI抑制生存素表达并诱导野生型p53和p53缺陷型卵巢癌细胞系中的程序性细胞死亡。这些数据表明GGTI-298和GGTI-2166通过靶向PI 3 K/AKT和存活素平行途径诱导凋亡，而不依赖于p53。由于Akt和生存素的上调以及p53的失活通常与化疗耐药性相关，GGTI可能是克服抗肿瘤药物耐药性的有价值的试剂。
Geranylgeranyltransferase I inhibitors (GGTIs) represent a new class of anticancer drugs. However, the mechanism by which GGTIs inhibit tumor cell growth is still unclear. Here, we demonstrate that GGTI-298 and GGTI-2166 induce apoptosis in both cisplatin-sensitive and -resistant human ovarian epithelial cancer cells by inhibition of PI3K/AKT and survivin pathways. Following GGTI-298 or GGTI-2166 treatment, kinase levels of PI3K and AKT were decreased and survivin expression was significantly reduced. Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis. Previous studies have shown that Akt mediates growth factor-induced survivin, whereas p53 inhibits survivin expression. However, constitutively active AKT2 failed to rescue the GGTIs downregulation of survivin. Further, GGTIs suppress survivin expression and induce programmed cell death in both wild-type p53 and p53-deficient ovarian cancer cell lines. These data indicate that GGTI-298 and GGTI-2166 induce apoptosis by targeting PI3K/AKT and survivin parallel pathways independent of p53. Owing to the fact that upregulation of Akt and survivin as well as inactivation of p53 are frequently associated with chemoresistance, GGTIs could be valuable agents to overcome antitumor drug resistance.