Dual blockade of phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways overcomes paclitaxel-resistance in colorectal cancer
Dual blockade of phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways overcomes paclitaxel-resistance in colorectal cancer
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DOI：
10.1016/j.canlet.2011.02.042
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发表时间：
2011-07-28
期刊：
影响因子：
9.7
通讯作者：
Katano, Mitsuo
中科院分区：
文献类型：
--
作者：
Xu, Rui;Nakano, Kenji;Katano, Mitsuo
紫杉醇是治疗多种恶性肿瘤的关键药物之一，对结直肠癌的敏感性相对较低。本研究旨在探讨磷脂酰肌醇3′-激酶（PI3K）信号是否以及如何影响结直肠癌对紫杉醇的敏感性。四种结直肠癌细胞系暴露于存在PI3K信号抑制剂（如LY294002， Akt siRNA，或rapamycin）的紫杉醇中，有或没有MAPK抑制剂PD98059。采用MTT法、流式细胞仪细胞周期分析和Hoechst核染色检测细胞活力和凋亡。为了分析PI3K的活性，采用Western blot分析磷酸化Akt及p70S6激酶（S6K）下游效应蛋白的表达。紫杉醇单独（5-10 nM）对4种细胞系均无诱导凋亡作用。虽然LY294002单独使用不影响细胞活力，但当紫杉醇和Akt siRNA和雷帕霉素联合使用时，LY294002抑制Akt和S6K活性，诱导亚g1阻滞/凋亡。同时阻断PI3K和MAPK通路更能抑制S6K活性，进一步增加细胞凋亡。综上所述，PI3K参与了结直肠癌对紫杉醇的低易感性，PI3K/MAPK双靶向药物可能发展出一种新的以紫杉醇为基础的结直肠癌化疗药物。2011爱思唯尔爱尔兰有限公司版权所有。
Paclitaxel, one of key drugs to treat a wide range of malignancies, exhibits relative low sensitivity for colorectal cancer. The present study was to examine whether and how phosphatidylinositol 3'-kinase (PI3K) signals affect the sensitivity of colorectal cancer to paclitaxel. Four colorectal cancer cell lines were exposed to paclitaxel in the presence of PI3K signal inhibitors, such as LY294002, siRNA for Akt, or rapamycicn, with or without MAPK inhibitor, PD98059. Cell viability and apoptosis were determined by MTT assay, cell cycle analysis in flow cytometer and Hoechst nuclear staining. To analyze the PI3K activity, the expression in phosphorylated Akt and downstream effectors of p70S6 kinase (S6K) were evaluated by Western blot analysis. Paclitaxel alone (5-10 nM) did not induce the apoptosis in all four cell lines. Although LY294002 alone did not affect the cell viability, it suppressed the Akt and S6K activities and induced the sub-G1 arrest/apoptosis when paclitaxel was co-administered, as well as the Akt siRNA and rapamycin did. Simultaneous blockade of PI3K and MAPK pathways more suppressed the S6K activity and further increased the apoptosis. In conclusion, PI3K is involved in low susceptibility of colorectal cancer to paclitaxel and dual PI3K/MAPK targeting agents may evolve a new paclitaxel-based chemotherapy for colorectal cancer. (C) 2011 Elsevier Ireland Ltd. All rights reserved.