Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death.
Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death.
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DOI：
10.1007/s10495-010-0542-4
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发表时间：
2011-01
期刊：
影响因子：
7.2
通讯作者：
Lin, Yong
中科院分区：
文献类型：
--
作者：
Bai, Lang;Xu, Shanling;Chen, Wenshu;Li, Zi;Wang, Xia;Tang, Hong;Lin, Yong
NF-κB 和 Akt 是减弱治疗抗癌功效的两种主要细胞存活途径。我们之前的研究表明，Smac 模拟化合物 3 (SMC3) 特异性抑制 c-IAP1 并诱导 TNF-α 自分泌来杀死癌细胞。然而，SMC3 还通过 NF-κB 激活诱导细胞生存信号。在本报告中，我们进一步发现 SMC3 有效激活 Akt，从而抑制 SMC3 诱导的癌细胞死亡。引人注目的是，同时阻断 NF-κB 和 Akt 导致细胞毒性显着增强。由于热休克蛋白 90 (Hsp90) 在维持癌细胞中 NF-κB 和 Akt 通路的完整性方面发挥着重要作用，因此我们研究了抑制 Hsp90 是否能够增强 SMC3 诱导的癌细胞死亡。结果表明，靶向 Hsp90 不会干扰 SMC3 诱导的 c-IAP1 降解和 TNF-α 自分泌，这是 SMC3 诱导癌细胞凋亡的关键过程。然而，Hsp90 抑制剂通过降解 NF-κB 激活途径的两个关键成分 RIP1 和 IKKβ，有效阻断 SMC3 诱导的 NF-κB 激活，并通过降解 Akt 蛋白降低组成型和 SMC3 诱导的 Akt 活性。一致的是，SMC3 和 Hsp90 抑制剂联合治疗时，细胞凋亡显着敏感，并观察到协同细胞毒性。结果表明，联合使用SMC3和Hsp90抑制剂同时靶向c-IAP1和Hsp90是提高SMC3抗癌价值的有效方法。
NF-κB and Akt are two main cell survival pathways that attenuate the anticancer efficacy of therapeutics. Our previous studies demonstrated that the Smac mimetic compound 3 (SMC3) specifically suppresses c-IAP1 and induces TNF-α autocrine to kill cancer cells. However, SMC3 also induces a cell survival signal through NF-κB activation. In this report, we further found that SMC3 potently activates Akt, which inhibits SMC3-induced cancer cell death. Strikingly, concurrent blocking NF-κB and Akt resulted in a significantly potentiated cytotoxicity. Because heat shock protein 90 (Hsp90) plays an important role in maintaining the integrity of both the NF-κB and Akt pathways in cancer cells, we examined if suppression of Hsp90 is able to potentiate SMC3-induced cancer cell death. The results show that targeting Hsp90 does not interfere with SMC3-induced c-IAP1 degradation and TNF-α autocrine, the key processes for SMC3-induced cancer cell apoptosis. However, Hsp90 inhibitors effectively blocked SMC3-induced NF-κB activation through degradation of RIP1 and IKKβ, two key components of the NF-κB activation pathway, and reduced both the constitutive and SMC3-induced Akt activity through degradation of the Akt protein. Consistently, with the co-treatment of SMC3 and Hsp90 inhibitors, apoptosis was markedly sensitized and a synergistic cytotoxicity was observed. The results suggest that concurrent targeting c-IAP1 and Hsp90 by combination of SMC3 and Hsp90 inhibitors is an effective approach for improving the anticancer value of SMC3.
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影响因子：
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