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

Marisa Granato, Celeste Rizzello, Maria Anele Romeo, Shivangi Yadav, Roberta Santarelli, Gabriella D'Orazi, Alberto Faggioni, Mara Cirone

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)393-400
Number of pages8
JournalInternational Journal of Biochemistry and Cell Biology
Volume79
DOIs
Publication statusPublished - Oct 1 2016

Keywords

  • Autophagy
  • BL
  • c-Myc
  • EBV
  • PI3K/AKT/mTOR
  • Quercetin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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