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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

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Abstract

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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Abbreviations

IAP:

Inhibitor of apoptosis protein

NF-κB:

Nuclear factor κB

Smac:

Second mitochondria-derived activator of caspase

SMC3:

Smac mimetic compound 3

TNF-α:

Tumor necrosis factor alpha

TNFR1:

TNF-α receptor 1

Hsp90:

Heat shock protein 90

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Acknowledgments

This study was partly supported by a grant from NIEHS/NIH (R01ES017328) and Department of Energy Low Dose Radiation Research Program (DE-SC0001173).

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Authors and Affiliations

  1. Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM, 87108, USA

    Lang Bai, Shanling Xu, Wenshu Chen, Zi Li & Yong Lin

  2. Infectious Disease Center, West China Hospital, Sichuan University, 37 Guoxuexiang, Chengdu, 610041, Sichuan, China

    Lang Bai & Hong Tang

  3. Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, 3-17 Renminnanlu, Chengdu, 610041, China

    Xia Wang

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  1. Lang Bai
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  2. Shanling Xu
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  3. Wenshu Chen
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  4. Zi Li
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  5. Xia Wang
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  6. Hong Tang
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  7. Yong Lin
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Corresponding author

Correspondence to Yong Lin.

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Lang Bai and Shanling Xu contributed equally.

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Bai, L., Xu, S., Chen, W. et al. Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death. Apoptosis 16, 45–54 (2011). https://doi.org/10.1007/s10495-010-0542-4

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  • DOI: https://doi.org/10.1007/s10495-010-0542-4

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