Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation.
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.
Farhana
Lulu
L
John D Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201, USA.
Dawson
Marcia I
MI
Fontana
Joseph A
JA
D016475:3T3 Cells; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D051996:Transcription Factor RelA; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D002934:Cinnamates; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505640:Tnfrsf10b protein, mouse; D051996:Transcription Factor RelA; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D019014:fas Receptor; D000072000:NF-KappaB Inhibitor alpha; D000218:Adamantane