Concomitant reduction of c-Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt's lymphoma. (October 2016)

• Record Type: Journal Article
• Authors: Granato, Marisa; Rizzello, Celeste; Romeo, Maria Anele; Yadav, Shivangi; Santarelli, Roberta; D'Orazi, Gabriella; Faggioni, Alberto; Cirone, Mara
• Is Part Of: International journal of biochemistry & cell biology. Volume 79(2016:Oct.)
• Page Start: 393
• Page End: 400
• Publication Date: 2016-10
• Subjects: Q quercetin -- BL Burkitt's lymphoma -- BCR B cell receptor -- GC Germinal Center -- EBV Epstein–Barr virus -- PI3K phosphatidylinositol-3-kinase -- AKT AKT or protein kinase B -- mTOR mammalian target of rapamycin -- BEZ235 NVP-BEZ235 -- I-c-Myc c-Myc inhibitor -- HSPs heat shock proteins -- PES 2-phenylethynesulfonamide -- CQ chloroquine -- PARP poly (ADP-ribose) polymerase -- LC3 microtubule-associated protein 1A/1B-light chain 3 -- 4E-BP1 eIF4E-binding protein -- c-Myc cellular myelocytomatosis oncogene -- NF-κB nuclear factor K-light-chain-enhancer of activated B cells -- Bcl-2 B-cell lymphoma 2 -- TCF-3 transcription factor 3 -- GSK3 glycogen synthase kinase 3 -- PES 2-phenylethyne-1-sulfonamide, 2-phenylethynesulfonamide; BL -- EBV -- Quercetin -- c-Myc -- PI3K/AKT/mTOR -- Autophagy; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2016.09.006
• Languages: English
• ISSNs: 1357-2725

Abstract

Abstract: Burkitt's lymphoma is an aggressive B cell lymphoma whose pathogenesis involves mainly c-Myc translocation and hyperexpression, in addition to antigen-independent BCR signaling and, in some cases, EBV infection. As result of BCR signaling activation, the PI3K/AKT/mTOR pathway results constitutively activated also in the absence of EBV, promoting cell survival and counterbalancing the pro-apoptotic function that c-Myc may also exert. In this study we found that quercetin, a bioflavonoid widely distributed in plant kingdom, reduced c-Myc expression and inhibited the PI3K/AKT/mTOR activity in BL, leading to an apoptotic cell death. We observed a higher cytotoxic effect against the EBV-negative BL cells in comparison with the positive ones, suggesting that this oncogenic gammaherpesvirus confers an additional resistance to the quercetin treatment. Besides cell survival, PI3K/AKT/mTOR pathway also regulates autophagy: we found that quercetin induced a complete autophagic flux in BL cells, that contributes to c-Myc reduction in some of these cells. Indeed, autophagy inhibition by chloroquine partially restored c-Myc expression in EBV-positive (Akata) and EBV-negative (2A8) cells that harbor c-Myc mutation. Interestingly, chloroquine did not affect the quercetin-mediated reduction of c-Myc expression in Ramos cells, that have no c-Myc mutation in the coding region, although autophagy was induced. These results suggest that mutant c-Myc could be partially degraded through autophagy in BL cells, as previously reported for other mutant oncogenic proteins.