title: Resveratrol-mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation.
abstract: Resveratrol (RSV), a plant-derived stilbene, induces cell death in Hodgkin lymphoma (HL)-derived L-428 cells in a dose-dependent manner (IC50 = 27 μM, trypan blue exclusion assay). At a lower range (25 μM), RSV treatment for 48 hr causes arrest in the S-phase of the cell cycle, while at a higher concentration range (50 μM), apoptosis can be detected, with activation of caspase-3. The histone/protein deacetylase SIRT1 has been described as a putative target of RSV action in other model systems, even though its role in cancer cells is still controversial. Here we show that RSV, at both concentration ranges, leads to a marked increase in p53, while a decrease of SIRT1 expression level, as well as enzyme activity, only occurred at the higher concentration range. Concomitantly, however, treatments at both concentration ranges resulted in a marked increase in K373-acetylated p53 and lysine-acetylated FOXO3a. Immunohistochemical stainings of human lymph nodes show a preferential distribution of SIRT1 in the germinal center of the follicles while the mantle zone shows nearly no staining to few positive cells. The classical HL-affected lymph nodes show a strong positivity of the diagnostic Hodgkin Reed-Sternberg cells. Notably, both the HL-derived cell lines and the Hodgkin Reed-Sternberg cells of the affected lymph nodes derive from germinal center-derived B cells. The study of SIRT1 distribution and expression on a larger number of biopsies might disclose a novel role for this histone/protein deacetylase as therapeutic target.
authors: Hematology Unit, Oncology Department, IRCCS - Arcispedale S. Maria Nuova, Reggio Emilia, Italy. raffaele.frazzi@asmn.re.it
authors: Raffaele
authors: R
authors: Frazzi
authors: Riccardo
authors: R
authors: Valli
authors: Ione
authors: I
authors: Tamagnini
authors: Bruno
authors: B
authors: Casali
authors: Norbert
authors: N
authors: Latruffe
authors: Francesco
authors: F
authors: Merli
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018858:Germinal Center / Q000187:drug effects / Q000378:metabolism; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D000077185:Resveratrol; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol