title: Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways.
abstract: Quercetin, a bioflavonoid contained in several vegetables daily consumed, has been studied for long time for its antiinflammatory and anticancer properties. Quercetin interacts with multiple cancer-related pathways such as PI3K/AKT, Wnt/β-catenin and STAT3. These pathways are hyperactivated in primary effusion lymphoma (PEL), an aggressive B cell lymphoma whose pathogenesis is strictly linked to the oncogenic virus Kaposis' Sarcoma-associated Herpesvirus (KSHV). In this study, we found that quercetin inhibited PI3K/AKT/mTOR and STAT3 pathways in PEL cells, and as a consequence, it down-regulated the expression of the prosurvival cellular proteins such as c-FLIP, cyclin D1 and cMyc. It also reduced the release of IL-6 and IL-10 cytokines, leading to PEL cell death. Moreover, quercetin induced a prosurvival autophagy in these cells and increased the cytotoxic effect of bortezomib, a proteasomal inhibitor, against them. Interestingly, quercetin decreased also the expression of latent and lytic KSHV proteins involved in PEL tumorigenesis and up-regulated the surface expression of HLA-DR and calreticulin, rendering the dying cells more likely detectable by the immune system. The results obtained in this study indicate that quercetin, which does not exert any cytotoxicity against normal B cells, may represent a good candidate for the treatment of this aggressive B cell lymphoma, especially in combination with autophagy inhibitors or with bortezomib.
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Granato
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: Rizzello
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
authors.forename: Maria Saveria
authors.initials: MS
authors.lastname: Gilardini Montani
authors.affiliation: U. O.C. Patologia Clinica, Ospedale San Filippo Neri, 00135 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cuomo
authors.affiliation: U. O.C. Patologia Clinica, Ospedale San Filippo Neri, 00135 Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Vitillo
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Santarelli
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gonnella
authors.affiliation: Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", 66013, Chieti, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Italy. Electronic address: alberto.faggioni@uniroma1.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Faggioni
authors.affiliation: Department of Experimental Medicine, "Sapienza" University of Rome, Italy. Electronic address: mara.cirone@uniroma1.it.
authors.forename: Mara
authors.initials: M
authors.lastname: Cirone
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000069286:Bortezomib / Q000819:agonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D054313:Drug Agonism; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011794:Quercetin / Q000009:adverse effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007378:Interleukins; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069286:Bortezomib; D011794:Quercetin; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Il-6; KSHV; PEL; Quercetin; STAT3; mTOR/PI3K/AKT