HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells.
HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells.
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DOI：
10.1016/j.cellsig.2014.11.013
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发表时间：
2015-02
影响因子：
4.8
通讯作者：
Lee YJ
中科院分区：
文献类型：
--
作者：
Lee DH;Sung KS;Bartlett DL;Kwon YT;Lee YJ
TRAIL已被证明可诱导癌细胞凋亡，但在某些情况下，某些癌细胞对该配体具有耐药性。在本研究中，我们探讨了具有代表性的热休克蛋白90(HSP90)抑制剂NVP-AUY922通过增加结直肠癌(CRC)细胞的凋亡来克服TRAIL耐药的能力。TRAIL与NVP-AUY922联合应用可诱导细胞协同杀伤和细胞凋亡，其机制可能是通过增加caspase活性来实现的。NVP-AUY922使JAK2和STAT3去磷酸化，降低Mcl-1，从而促进细胞色素c的释放。NVP-AUY922对JAK2/STAT3信号通路的抑制及其靶基因Mcl-1的下调呈剂量和时间依赖关系。敲除Mcl-1、STAT3抑制剂或JAK2抑制剂协同增强TRAIL诱导的细胞凋亡。综上所述，我们的结果提示JAK2-STAT3-Mcl-1信号转导通路参与了NVP-AUY922对TRAIL的反应，这可能在NVP-AUY922介导的TRAIL增敏中起关键作用。相比之下，联合治疗对未转化的结肠细胞的影响微乎其微。我们提供了HSP90抑制剂联合TRAIL在不增加正常组织毒性的情况下提高结直肠癌患者治疗效果的临床理论依据。
TRAIL has been shown to induce apoptosis in cancer cells, but in some cases certain cancer cells are resistant to this ligand. In this study, we explored the ability of representative HSP90 (heat shock protein 90) inhibitor NVP-AUY922 to overcome TRAIL resistance by increasing apoptosis in colorectal cancer (CRC) cells. The combination of TRAIL and NVP-AUY922 induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The treatment of NVP-AUY922 dephosphorylated JAK2 and STAT3 and decreased Mcl-1 which resulted in facilitating cytochrome c release. NVP-AUY922-mediated inhibition of JAK2/STAT3 signaling and down-regulation of their target gene, Mcl-1, occurred in a dose and time-dependent manner. Knock down of Mcl-1, STAT3 inhibitor or JAK2 inhibitor synergistically enhanced TRAIL-induced apoptosis. Taken together, our results suggest the involvement of the JAK2-STAT3-Mcl-1 signal transduction pathway in response to NVP-AUY922 treatment, which may play a key role in NVP-AUY922-mediated sensitization to TRAIL. In contrast, the effect of the combination treatments in non-transformed colon cells was minimal. We provide a clinical rationale that combining HSP90 inhibitor with TRAIL enhances therapeutic efficacy without increasing normal tissue toxicity in CRC patients.
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影响因子：
3.8
作者：
Lee, Dae-Hee;Kim, Dong-Wook;Jung, Chang-Hwa;Lee, Yong J.;Park, Daeho
通讯作者：
Park, Daeho
DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
影响因子：
15.9
作者：
Epling-Burnette, PK;Liu, JH;Loughran, TP
通讯作者：
Loughran, TP
影响因子：
5.8
作者：
Lu, Xiangyi;Xiao, Li;Wang, Luan;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
抑制JAK2/STAT3信号通过线粒体途径诱导结直肠癌细胞凋亡
影响因子：
5.3
作者：
Du W;Hong J;Wang YC;Zhang YJ;Wang P;Su WY;Lin YW;Lu R;Zou WP;Xiong H;Fang JY
通讯作者：
Fang JY