Pim-1 plays a pivotal role in hypoxia-induced chemoresistance.
Pim-1 plays a pivotal role in hypoxia-induced chemoresistance.
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DOI：
10.1038/onc.2009.124
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发表时间：
2009-07-16
期刊：
影响因子：
8
通讯作者：
Lee, M. H.
中科院分区：
文献类型：
--
作者：
Chen, J.;Kobayashi, M.;Darmanin, S.;Qiao, Y.;Gully, C.;Zhao, R.;Yeung, S. C.;Lee, M. H.
缺氧改变了癌细胞对许多化疗药物的反应，导致化疗耐药性。低氧诱导耐药的分子机制尚不清楚。Pim-1是一种存活激酶，其在丝氨酸112处磷酸化Bad以拮抗药物诱导的细胞凋亡。在这里，我们表明，缺氧增加Pim-1在HIF-1α-独立的方式。在体外和体内肿瘤模型中，显性阴性Pim-1对Pim-1功能的抑制显著恢复了对缺氧条件下化疗诱导的细胞凋亡的药物敏感性。Pim-1的siRNA的引入也使癌细胞在缺氧条件下对化疗药物重新敏感，而Pim-1的强制过表达赋予实体瘤细胞对顺铂的抗性，即使在常氧条件下。显性负性Pim-1阻止了CDDP通常诱导的实体瘤细胞线粒体跨膜电位的降低，随后是Caspase-3和Caspase-9活性的降低，表明Pim-1通过稳定线粒体跨膜电位参与了缺氧诱导的耐药。我们的研究结果表明，Pim-1是一个关键的调节参与缺氧诱导的化疗耐药性。靶向Pim-1可能改善实体瘤的化疗策略。
Hypoxia changes the responses of cancer cells to many chemotherapy agents, resulting in chemoresistance. The underlying molecular mechanism of hypoxia-induced drug resistance remains unclear. Pim-1 is a survival kinase which phosphorylates Bad at serine 112 to antagonize drug induced apoptosis. Here we show that hypoxia increases Pim-1 in a HIF-1α-independent manner. Inhibition of Pim-1 function by dominant negative Pim-1 dramatically restores the drug sensitivity to apoptosis induced by chemotherapy under hypoxic conditions in both in vitro and in vivo tumor models. Introduction of siRNAs for Pim-1 also resensitizes cancer cells to chemotherapy drugs under hypoxic conditions, while forced over-expression of Pim-1 endowes solid tumor cells with resistance to cisplatin, even under normoxia. Dominant negative Pim-1 prevents a decrease in mitochondrial transmembrane potential in solid tumor cells, which is normally induced by CDDP, followed by the reduced activity of Caspase-3 and -9, indicating that Pim-1 participates in hypoxia-induced drug resistance through the stabilization of mitochondrial transmembrane potential. Our results demonstrate that Pim-1 is a pivotal regulator involved in hypoxia-induced chemoresistance. Targeting Pim-1 may improve the chemotherapeutic strategy for solid tumors.
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影响因子：
2.8
作者：
Valdman, A;Fang, XL;Egevad, L
通讯作者：
Egevad, L
影响因子：
11.2
作者：
C치rdenas-Navia, LI;Yu, DH;Dewhirst, MW
通讯作者：
Dewhirst, MW
DOI：
10.1016/0360-3016(92)91001-4
发表时间：
1992-01-01
影响因子：
7
作者：
KOH, WJ;RASEY, JS;GRIFFIN, TW
通讯作者：
GRIFFIN, TW
影响因子：
8.8
作者：
Niizeki, H;Kobayashi, M;Horiuchi, I;Akakura, N;Chen, J;Wang, J;Hamada, J;Seth, P;Katoh, H;Watanabe, H;Raz, A;Hosokawa, M
通讯作者：
Hosokawa, M
影响因子：
64.5
作者：
SELTEN, G;CUYPERS, HT;BERNS, A
通讯作者：
BERNS, A