title: Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through             upregulation of the BH3-only protein Noxa.
abstract: We previously reported that hyperforin, a phloroglucinol purified from Hypericum             perforatum, induces the mitochondrial pathway of caspase-dependent apoptosis in             chronic lymphocytic leukemia (CLL) cells ex vivo, and that this effect is associated             with upregulation of Noxa, a BH3-only protein of the Bcl-2 family. Here, we investigated             the role of this upregulation in the pro-apoptotic activity of hyperforin in the             cells of CLL patients and MEC-1 cell line. We found that the increase in Noxa             expression is a time- and concentration-dependent effect of hyperforin occurring             without change in Noxa mRNA levels. A post-translational regulation is suggested             by the capacity of hyperforin to inhibit proteasome activity in CLL cells. Noxa             silencing by siRNA reduces partially hyperforin-elicited apoptosis. Furthermore,             treatment with hyperforin, which has no effect on the expression of the prosurvival             protein Mcl-1, induces the interaction of Noxa with Mcl-1 and the dissociation             of Mcl-1/Bak complex, revealing that upregulated Noxa displaces the proapoptotic             protein Bak from Mcl-1. This effect is accompanied with Bak activation, known             to allow the release of apoptogenic factors from mitochondria. Our data indicate             that Noxa upregulation is one of the mechanisms by which hyperforin triggers CLL             cell apoptosis. They also favor that new agents capable of mimicking specifically             the BH3-only protein Noxa should be developed for apoptosis-based therapeutic             strategy in CLL.
authors.affiliation: Centre de Recherche des Cordeliers, INSERM U872, Equipe 18, Paris,                     France.
authors.forename: Murhaf
authors.initials: M
authors.lastname: Zaher
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bombarda
authors.forename: Faten
authors.initials: F
authors.lastname: Merhi
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bauvois
authors.forename: Christian
authors.initials: C
authors.lastname: Billard
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013729:Terpenes / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013729:Terpenes; D050998:bcl-2 Homologous Antagonist-Killer Protein; D010696:Phloroglucinol; C001654:hyperforin