MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells.
MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells.
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DOI：
10.1021/mp900321a
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发表时间：
2010-10-04
影响因子：
4.9
通讯作者：
Sun D
中科院分区：
文献类型：
--
作者：
Zhang T;Li Y;Zhu Z;Gu M;Newman B;Sun D
RAS/Raf/MEK/ERK信号转导通路参与了胰腺癌细胞增殖失控和肿瘤进展。本研究旨在评价MEK抑制剂U0126联合Hsp90抑制剂17-烯丙氨基-17-去甲氧基格尔达那霉素(17-AAG)对胰腺癌细胞的抗肿瘤活性。Western blotting显示，17-AAG导致胰腺癌细胞MEK/ERK信号的瞬时激活2-3倍。激活持续6h后，磷酸化ERK(p-ERK)失稳。选择性MEK抑制剂U0126可完全阻断17-AAG诱导的ERK1/2激活，仅作用15min，ERK的磷酸化降解率达80%以上。此外，U0126对17-AAG调控的致癌蛋白和细胞周期相关蛋白具有互补作用。17-AAG虽然下调了细胞周期蛋白D1、细胞周期蛋白E、细胞周期蛋白CDK4和细胞周期蛋白CDK6的表达，但却导致细胞周期蛋白A和细胞周期蛋白CDK2的积聚，而U0126的加入则逆转了这一作用。抗增殖实验表明，U0126与17-AAG联合应用具有协同细胞毒作用。更重要的是，单独的17-AAG在体外对细胞迁移的抑制作用只是中等程度的，而U0126的加入则显著增强了这种抑制作用2-5倍。综上所述，这些数据表明，MEK抑制剂U0126增强了Hsp90抑制剂17-AAG对胰腺癌细胞的活性。Hsp90和MEK抑制的联合应用可能为胰腺癌的治疗提供一条很有前途的途径。
The Ras/Raf/MEK/ERK signaling has been implicated in uncontrolled cell proliferation and tumor progression in pancreatic cancer. The purpose of this study is to evaluate the antitumor activity of MEK inhibitor U0126 in combination with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in pancreatic cancer cells. Western blotting showed that 17-AAG caused a 2- to 3-fold transient activation of MEK/ERK signaling in pancreatic cancer cells. The activation sustained for 6 h before phospho-ERK (p-ERK) destabilization. The selective MEK inhibitor U0126 completely abolished 17-AAG induced ERK1/2 activation and resulted in more than 80% of phosphor-ERK degradation after only 15 min treatment. Moreover, U0126 had complementary effect on 17-AAG regulated oncogenic and cell cycle related proteins. Although 17-AAG downregulated cyclin D1, cyclin E, CDK4 and CDK6, it led to cyclin A and CDK2 accumulation, which was reversed by the addition of U0126. Anti-proliferation assay showed that combination of U0126 and 17-AAG resulted in synergistic cytotoxic effect. More importantly, 17-AAG alone only exhibited moderate inhibition of cell migration in vitro, while addition of U0126 dramatically enhanced the inhibitory effect by 2- to 5-fold. Taken together, these data demonstrate that MEK inhibitor U0126 potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. The combination of Hsp90 and MEK inhibition could provide a promising avenue for the treatment of pancreatic cancer.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
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影响因子：
11.5
作者：
Cao, Xianhua;Bloomston, Mark;Sun, Duxin
通讯作者：
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影响因子：
4.8
作者：
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影响因子：
7
作者：
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Pandey, A
DOI：
10.1073/pnas.95.3.1091
发表时间：
1998-02-03
影响因子：
11.1
作者：
Cheng, MG;Sexl, V;Roussel, MF
通讯作者：
Roussel, MF