Inducible P27Kip1 expression inhibits proliferation of K562 cells and protects against apoptosis induction by proteasome inhibitors
Inducible P27Kip1 expression inhibits proliferation of K562 cells and protects against apoptosis induction by proteasome inhibitors
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DOI：
10.1038/sj.cdd.4401159
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发表时间：
2003-03-01
影响因子：
12.4
通讯作者：
Pebler, S
中科院分区：
文献类型：
--
作者：
Drexler, HCA;Pebler, S
细胞周期蛋白依赖性激酶抑制因子P27(Kip1)的过表达可诱导多种肿瘤细胞系的细胞周期停滞和细胞凋亡，但也与肿瘤细胞的存活和化疗耐药性增加的相反作用有关。为了探讨p27(KIP1)的表达与诱导细胞凋亡的关系，我们研究了多西环素调控的p27(KIP1)在K562红白血病细胞中的表达。P27(KIP1)的表达有效地抑制了K562细胞的增殖，但不足以诱导K562细胞的凋亡。然而，表达p27(Kip1)的K562细胞对蛋白酶体抑制剂PSI、MG132和环氧米星诱导的凋亡具有抵抗力，而野生型K562细胞则被有效地杀死。蜂毒灵使细胞周期停滞于S期，与细胞蓄积无关。P27(Kip1)蛋白不能保护K562细胞免受蛋白酶体抑制剂PSI的细胞毒作用。因此，p27(Kip1)的表达水平构成了一个重要的参数，它决定了细胞对蛋白酶体抑制剂细胞毒作用的总体敏感性。
Overexpression of the cyclin-dependent kinase inhibitor P27(Kip1) has been demonstrated to induce cell cycle arrest and apoptosis in various cancer cell lines, but has also been associated with the opposite effect of enhanced survival of tumor cells and increased resistance towards chemotherapeutic treatment. To address the question of how p27(KIP1) expression is related to apoptosis induction, we studied doxycycline-regulated p27(KiP1) expression in K562 erythroleukemia cells. p27(KiP1) expression effectively retards proliferation, but it is not sufficient to induce apoptosis in K562 cells. p27(Kip1)-expressing K562 cells, however, become resistant to apoptosis induction by the proteasome inhibitors PSI, MG132 and epoxomicin, in contrast to wild-type K562 cells that are efficiently killed. Cell cycle arrest in the S phase by aphidicolin, which is not associated with an accumulation. of p27(Kip1) protein, did not protect K562 cells against the cytotoxic effect of the proteasome inhibitor PSI. The expression levels of p27(Kip1) thus constitute an important parameter, which decides on the overall sensitivity of cells against the cytotoxic effect of proteasome inhibitors.