Proteasome-dependent degradation of Chk1 kinase induced by the topoisomerase II inhibitor R16 contributes to its anticancer activity
Proteasome-dependent degradation of Chk1 kinase induced by the topoisomerase II inhibitor R16 contributes to its anticancer activity
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DOI：
10.4161/cbt.7.11.6728
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发表时间：
2008-11-01
影响因子：
3.6
通讯作者：
Miao, Ze-Hong
中科院分区：
文献类型：
--
作者：
Feng, Jian-Ming;Zhu, Hong;Miao, Ze-Hong
The novel naphthalimide derivative R16 has been demonstrated to exhibit potent in vitro and in vivo anticancer activity by inhibiting topoisomerase II (Top2). R16 induces G(2) arrest via an ATM-activated Chk2-executed pathway, accompanied by reducing Chk1. In this study, R16 was demonstrated to trigger time and concentration-dependent Chk1 reduction which was unrelated to the mRNA level and HSP90-involved degradation. Pretreatment of HCT116 cells with the proteasome inhibitors MG132 or lactacystin prevented Chk1 decline induced by R16, accompanied by significant accumulation of ubiquitinated Chk1 protein, indicating the involvement of ubiquitin-proteasome pathway. Meanwhile, R16 also resulted in loss of Chk1 function. By site-specifically mutating the phosphorylation sites of Chk1 protein at Ser317 or at Ser345, we further demonstrated that R16-triggered Chk1 reduction was associated with its apoptotic induction and cell killing. In conclusion, the data reveal that the novel Top2 inhibitor R16 induces degradation of Chk1 via the ubiquitin-proteasome pathway, impairing the function of Chk1 and thus contributing to the anticancer activity of R16.
