A synthetic bichalcone analog, (E)-1-(3-((4-(4- acetylphenyl)piperazin-1-yl)methyl)-4-hydroxy-5- methoxyphenyl)-3-(pyridin-3-yl)prop-2-en-1-one (TSWUBR23), has been shown to induce apoptosis in human colon cancer HT-29 cells involving the induction of CD95 and FASassociated protein death domain (FADD), but its precise mechanism of action has not been fully elucidated. Using cell-surface biotinylation and sucrose density-gradient-based membrane flotation techniques, we showed that the disruption of TSWU-BR23-induced lipid raft localization of CD95/FADD by cholesterol-depleting agent (methyl-β-cyclodextrin) was reversed by cholesterol replenishment. Blockade of p53 expression by short-hairpin RNA (shRNA) suppressed oligomeric Bcl-2-associated x protein (BAX)/Bcl-2 antagonist killer 1 (BAK)-mediated mitochondrial apoptosis but did not inhibit lipid raft localization of CD95/FADD and procaspase- 8 cleavage induced by TSWU-BR23. Co-expression of p53 shRNA and dominant-negative mutant of FADD completely inhibited TSWU-BR32-induced mitochondrial apoptotic cell death. Collectively, these data demonstrate that TSWU-BR23 leads to HT-29 cell apoptosis by inducing p53- mediated mitochondrial oligomerization of BAX/BAK and the localization of CD95/FADD with lipid rafts at the cell surface.
|頁（從 - 到）||5407-5416|
|出版狀態||Published - 2015 十月 1|
All Science Journal Classification (ASJC) codes
- Cancer Research