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Istituto di scienza dell'alimentazione

Torna all'elenco Contributi in rivista anno 2011

Contributo in rivista

Tipo: Articolo in rivista

Titolo: Quercetin downregulates Mcl-1 by acting on mRNA stability and protein degradation

Anno di pubblicazione: 2011

Formato: Elettronico Cartaceo

Autori: Spagnuolo C, Cerella C, Russo M, Chateauvieux S, Diederich M, Russo GL.

Affiliazioni autori: Istituto Scienze dell'Alimentazione LBMCC, Luxemburg

Autori CNR:

  • GIAN LUIGI RUSSO
  • MARIA RUSSO
  • CARMELA SPAGNUOLO
  • IDOLO TEDESCO

Lingua: inglese

Abstract: Abstract BACKGROUND: We recently demonstrated that quercetin, a flavonoid naturally present in food and beverages belonging to the large class of phytochemicals, was able to sensitise leukaemic cells isolated from patients with chronic lymphocytic leukaemia (CLL) when associated with recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) or anti-CD95. We also showed that quercetin potentiated the effect of fludarabine on resistant B cells from CLL patients. Resistance to therapy in CLL depends on the expression and activity of anti-apoptotic proteins of the Bcl-2 family. Among these, myeloid cell leukaemia-1 (Mcl-1) has been associated with apoptotic resistance in CLL. Therefore, we investigate here whether the sensitising activity of this flavonoid, which leads to increased apoptosis in both cell lines and CLL, could be related to Mcl-1 expression and stability. RESULTS: B cells isolated from CLL patients showed different levels of Mcl-1 protein expression, resulting, in several cases, in increased sensitivity to fludarabine. Quercetin significantly enhanced the downregulation of Mcl-1 in B cells isolated from selected patients expressing detectable levels of Mcl-1. In U-937 cells, quercetin increased Mcl-1 mRNA instability in the presence of actinomycin D. When cells were treated with MG-132, a proteasome inhibitor, Mcl-1 protein level increased. However, quercetin, in the presence of Z-Vad-FMK, continued to lower Mcl-1 protein expression, indicating its independence from caspase-mediated degradation. In contrast, co-treatment of quercetin and MG-132 did not revert the effect of MG-132 mono-treatment, thus suggesting a possible interference of quercetin in regulating the proteasome-dependent degradation of Mcl-1. Gossypol, a small-molecule inhibitor of Bcl-2 family members, mimics the activity of quercetin by lowering Mcl-1 expression and sensitising U-937 cells to apoptosis induced by recombinant TRAIL and the Fas-ligand. CONCLUSION: This study demonstrates that in U-937 cells, quercetin downregulates Mcl-1 acting directly or indirectly on its mRNA stability and protein degradation, suggesting that the same mechanism may bypass resistance to apoptosis in leukaemic cells isolated from CLL patients and sensitise B cells to apoptosis induced by drugs and death receptor inducers.

Lingua abstract: inglese

Pagine da: 221

Pagine a: 230

Rivista:

British Journal of Cancer H K Lewis and Co, Ltd.
Paese di pubblicazione: Regno Unito
Lingua: inglese
ISSN: 0007-0920

Numero volume: 105

Numero fascicolo: 2

Referee: Sė: Internazionale

Stato della pubblicazione: Published version

Indicizzato da: PubMed [21750559]

Parole chiave:

  • quercetin
  • chronic leukemia
  • Apoptosis
  • therapy

Altre informazioni: PubMed Link: http://www.ncbi.nlm.nih.gov/pubmed/21750559

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