Concomitant reduction of c-Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt's lymphoma.
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.
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
Marisa
M
Granato
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
Celeste
C
Rizzello
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
Maria Anele
MA
Romeo
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
Shivangi
S
Yadav
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
Roberta
R
Santarelli
Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti, Italy.
Gabriella
G
D'Orazi
Department of Experimental Medicine, "Sapienza" University of Rome, Italy. Electronic address: alberto.faggioni@uniroma1.it.
Alberto
A
Faggioni
Department of Experimental Medicine, "Sapienza" University of Rome, Italy. Electronic address: mara.cirone@uniroma1.it.
Mara
M
Cirone
D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011794:Quercetin; D058570:TOR Serine-Threonine Kinases
Autophagy; BL; EBV; PI3K/AKT/mTOR; Quercetin; c-Myc