Abstract
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) and 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) are inducers of apoptosis of malignant cells both in vitro and in vivo. Numerous mechanisms have been proposed for how these compounds exert this effect. This report shows that AHPN/3-Cl-AHPC binds specifically to the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), and this binding promotes interaction of the receptor with a corepressor complex that minimally contains Sin3A, N-CoR, histone deacetylase 4, and HSP90. Formation of the SHP-Sin3A complex is essential for the ability of AHPN and 3-Cl-AHPC to induce apoptosis, as both knockout SHP and knockdown of Sin3A compromise the proapoptotic activity of these compounds but not other apoptosis inducers. These results suggest that AHPN/3-Cl-AHPC and their analogues are SHP ligands and their induction of apoptosis is mediated by their binding to the SHP receptor.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adamantane / analogs & derivatives*
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Adamantane / metabolism
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Adamantane / pharmacology
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Adenosine Triphosphatases / metabolism
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Line, Tumor
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Cinnamates / metabolism*
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Cinnamates / pharmacology
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HSP90 Heat-Shock Proteins / metabolism
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Histone Deacetylases / metabolism
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Humans
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Naphthalenes / metabolism*
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Naphthalenes / pharmacology
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Protein Binding
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Proto-Oncogene Proteins c-myc / biosynthesis
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Repressor Proteins / metabolism*
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Sin3 Histone Deacetylase and Corepressor Complex
Substances
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4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
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6-(3'-(1-adamantyl)-4'-hydroxyphenyl)-5-chloronaphthalenecarboxylic acid
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Cinnamates
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HSP90 Heat-Shock Proteins
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MYC protein, human
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Naphthalenes
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Proto-Oncogene Proteins c-myc
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Receptors, Cytoplasmic and Nuclear
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Repressor Proteins
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SIN3A transcription factor
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nuclear receptor subfamily 0, group B, member 2
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Histone Deacetylases
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Sin3 Histone Deacetylase and Corepressor Complex
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Adenosine Triphosphatases
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Adamantane