Quercetin affects Hsp70/IRE1α mediated protection from death induced by endoplasmic reticulum stress.
Relative to their normal counterparts, tumor cells generally exhibit a greater "stress phenotype" and express heat shock proteins (Hsp) that represent candidate targets for anticancer therapy. Here we investigated the role of Hsp70 in survival induced by endoplasmic reticulum (ER) stressors in human leukemia U937 cells. Quercetin, a major dietary flavonoid, or specific silencing affected the expression level of Hsp70 and did not allow the upregulation of inositol-requiring kinase 1α (IRE1α), the prototype ER stress sensor regulating the unfolded protein response (UPR), that protects the cells against the stress of misfolded proteins in the ER. The reduction of Hsp70 prevented the upregulation of immunoglobulin heavy-chain binding protein (BiP), but not of CCAAT/enhancer-binding protein-homologous protein (CHOP), and induced apoptosis. Also specific silencing of IRE1α or inhibition of its endoribonuclease activity by 4μ8c hampered the upregulation of BiP, but not of CHOP, and induced apoptosis. These results suggest that drugs affecting the Hsp70-IRE1α axis, like quercetin, or affecting directly IRE1α may represent an effective adjuvant antileukemia therapy.
Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy.
Antonello
A
Storniolo
Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy.
Marisa
M
Raciti
Department of Surgery P. Valdoni, Sapienza University, Via A. Scarpa 14, 00161 Rome, Italy.
Alessandra
0000-0001-5469-6419
A
Cucina
Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy.
Mariano
0000-0003-0408-4136
M
Bizzarri
Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy.
Livia
L
Di Renzo
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D019284:Thapsigargin / Q000633:toxicity; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin / Q000633:toxicity; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000975:Antioxidants; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D019284:Thapsigargin; D011794:Quercetin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases