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Resveratrol‐mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation
Author(s) -
Frazzi Raffaele,
Valli Riccardo,
Tamagnini Ione,
Casali Bruno,
Latruffe Norbert,
Merli Francesco
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27748
Subject(s) - apoptosis , germinal center , mantle zone , cancer research , cell cycle , acetylation , resveratrol , lymph , lymphoma , reed–sternberg cell , histone deacetylase , biology , mantle cell lymphoma , chemistry , histone , antibody , medicine , pathology , immunology , b cell , biochemistry , hodgkin lymphoma , gene
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.