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首页> 外文期刊>Apoptosis >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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Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death

机译：通过Hsp90抑制来阻断NF-κB和Akt使Smac模拟化合物3诱导的外源性凋亡途径致敏并导致协同的癌细胞死亡

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摘要

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.
机译：NF-κB和Akt是削弱治疗剂抗癌功效的两个主要细胞存活途径。我们以前的研究表明，Smac模拟化合物3（SMC3）特异性抑制c-IAP1并诱导TNF-α自分泌杀死癌细胞。但是，SMC3还通过NF-κB激活诱导细胞存活信号。在此报告中，我们进一步发现SMC3可以有效激活Akt，从而抑制SMC3诱导的癌细胞死亡。令人惊讶的是，同时阻断NF-κB和Akt导致明显增强的细胞毒性。因为热休克蛋白90（Hsp90）在维持癌细胞中NF-κB和Akt通路的完整性中起着重要作用，所以我们检查了对Hsp90的抑制是否能够增强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诱导的癌细胞凋亡的关键过程。但是，Hsp90抑制剂通过降解NF-κB激活途径的两个关键成分RIP1和IKKβ来有效阻断SMC3诱导的NF-κB激活，并通过Akt蛋白的降解降低了本构和SMC3诱导的Akt活性。一致地，与SMC3和Hsp90抑制剂共同治疗，细胞凋亡明显敏化，并观察到协同的细胞毒性。结果表明，通过同时使用SMC3和Hsp90抑制剂同时靶向c-IAP1和Hsp90是提高SMC3的抗癌价值的有效方法。

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