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

J Nutr Biochem. 2017 Mar:41:124-136. doi: 10.1016/j.jnutbio.2016.12.011. Epub 2017 Jan 5.


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.

Keywords: Il-6; KSHV; PEL; Quercetin; STAT3; mTOR/PI3K/AKT.

Publication types

  • Comparative Study

MeSH terms

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


  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Interleukins
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteasome Inhibitors
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Bortezomib
  • Quercetin
  • MTOR protein, human
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases