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. 2011 Jan;16(1):45-54. doi: 10.1007/s10495-010-0542-4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Synergism
  • Gene Expression
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / pharmacology*
  • Liver Neoplasms / metabolism
  • Lung Neoplasms / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mitochondrial Proteins / pharmacology*
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / pharmacology*
  • Rifabutin / pharmacology*
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
  • X-Linked Inhibitor of Apoptosis Protein / metabolism


  • Apoptosis Regulatory Proteins
  • CCT018159
  • DIABLO protein, human
  • HSP90 Heat-Shock Proteins
  • Heterocyclic Compounds, 2-Ring
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • NF-kappa B
  • Pyrazoles
  • Tumor Necrosis Factor-alpha
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Rifabutin
  • Proto-Oncogene Proteins c-akt
  • I-kappa B Kinase