Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways

M. Granato, C. Rizzello, M. S. Gilardini Montani, L. Cuomo, M. Vitillo, R. Santarelli, R. Gonnella, G. D'Orazi, A. Faggioni, M. Cirone

Research output: Contribution to journalArticle

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/beta-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.
Original languageEnglish
Pages (from-to)124-136
Number of pages13
JournalJournal of Nutritional Biochemistry
Volume41
DOIs
Publication statusPublished - Mar 1 2017

Keywords

  • Antineoplastic Agents/chemistry/pharmacology
  • Antineoplastic Agents, Phytogenic/adverse effects/metabolism
  • Apoptosis/drug effects
  • Autophagy/drug effects
  • B-Lymphocytes/cytology/drug effects/immunology/metabolism
  • Bortezomib/agonists/pharmacology
  • Cell Line, Tumor
  • Cells, Cultured
  • Down-Regulation/drug effects
  • Drug Agonism
  • Humans
  • Interleukins/antagonists & inhibitors/metabolism
  • Lymphoma, Primary Effusion/drug therapy/immunology/metabolism/pathology
  • Neoplasm Proteins/antagonists & inhibitors/metabolism
  • Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolism
  • Proteasome Inhibitors/chemistry/pharmacology
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
  • Quercetin/adverse effects/metabolism
  • Recombinant Fusion Proteins/chemistry/genetics/metabolism
  • STAT3 Transcription Factor/antagonists & inhibitors/metabolism
  • Signal Transduction/drug effects
  • TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
  • Il-6
  • KSHV
  • PEL
  • Quercetin
  • STAT3
  • mTOR/PI3K/AKT

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  • Cite this

    Granato, M., Rizzello, C., Montani, M. S. G., Cuomo, L., Vitillo, M., Santarelli, R., Gonnella, R., D'Orazi, G., Faggioni, A., & Cirone, M. (2017). Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. Journal of Nutritional Biochemistry, 41, 124-136. https://doi.org/S0955-2863(16)30178-4 [pii]