Abstract
Nuclear factor-kappaB (NF-kappaB) activation has been shown to be both antiapoptotic and proapoptotic depending on the stimulus and the specific cell type involved. NF-kappaB activation has also been shown to be essential for apoptosis induction by a number of agents. The novel retinoid-related molecule 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) activates NF-kappaB with subsequent apoptosis in a number of cell types. We have found that NF-kappaB activation is essential for 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC activates NF-kappaB through IKKalpha kinase activation and the subsequent degradation of IkappaB alpha. IKKalpha kinase activation is associated with IKKalpha-enhanced binding to HSP90. The HSP90 inhibitor geldanamycin enhances the degradation of IKKalpha and blocks 3-Cl-AHPC activation of NF-kappaB and 3-Cl-AHPC-mediated apoptosis. In addition, inhibition of IkappaB alpha degradation using a dominant-negative IkappaB alpha inhibits 3-Cl-AHPC-mediated apoptosis. NF-kappaB p65 activation is essential for 3-Cl-AHPC apoptosis induction as evidenced by the fact that inhibition of p65 activation utilizing the inhibitor helenalin or loss of p65 expression block 3-Cl-AHPC-mediated apoptosis. NF-kappaB has been shown to be antiapoptotic through its enhanced expression of a number of antiapoptotic proteins including X-linked inhibitor of apoptosis protein (XIAP), c-IAP1, and Bcl-X(L). Whereas exposure to 3-Cl-AHPC results in NF-kappaB activation, it inhibits the expression of XIAP, c-IAP1, and Bcl-X(L) and enhances the expression of proapoptotic molecules, including the death receptors DR4 and DR5 as well as Fas and Rip1. Thus, 3-Cl-AHPC, which is under preclinical development, has pleotrophic effects on malignant cells resulting in their apoptosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Adamantane / analogs & derivatives*
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Adamantane / pharmacology*
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Animals
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Apoptosis / drug effects*
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Apoptosis / physiology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cinnamates / pharmacology*
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Humans
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I-kappa B Proteins / biosynthesis
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I-kappa B Proteins / genetics
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I-kappa B Proteins / physiology
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Male
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Mice
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / biosynthesis
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NF-kappa B / genetics
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NF-kappa B / metabolism
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NF-kappa B / physiology*
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proteins / antagonists & inhibitors
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / genetics
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Transcription Factor RelA
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X-Linked Inhibitor of Apoptosis Protein
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bcl-X Protein
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fas Receptor / biosynthesis
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fas Receptor / genetics
Substances
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4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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Cinnamates
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, mouse
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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TNFRSF10A protein, human
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TNFRSF10B protein, human
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Tnfrsf10b protein, mouse
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Transcription Factor RelA
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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bcl-X Protein
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fas Receptor
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NF-KappaB Inhibitor alpha
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Adamantane