Xanthohumol activates the proapoptotic arm of the unfolded protein response in chronic lymphocytic leukemia.
BACKGROUND
Chronic lymphocytic leukemia (CLL) is an incurable disease with a natural history of increasing resistance to chemotherapy. A novel approach to overcome chemotherapy resistance may be targeting the endoplasmic reticulum (ER).


METHODS
The involvement of the unfolded protein response (UPR) in the cell killing effect of xanthohumol (X) was examined in 18 patient samples.


RESULTS
X-induced apoptosis of CLL cells was accompanied by the induction of glucose-regulated protein of 78 kDa (GRP78) and heat-shock protein of 70 kDa (Hsp70) protein levels and by sustained phosphorylation of the eukaryotic translation initiation factor 2 (eIF2alpha), suggesting the involvement of the ER stress transducer, the double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK). The X-box-binding protein 1 (XBP1) mRNA was spliced but no clear activation of activating transcription factor 6 (ATF6) was observed. The proapoptotic outcome was further demonstrated by the up-regulation of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), down-regulation of myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2), cleavage of poly-(ADP)-ribose polymerase (PARP) and processing of caspase-3, -4 and -9. Furthermore, X showed proteasome inhibitory activity.


CONCLUSIONS
X stimulates the proapoptotic arm of the UPR in ex vivo CLL cells, suggesting that ER stress may play an important role during X-induced apoptosis.
Ghent University Hospital, Department of Hematology, De Pintelaan 185, 1P7, B-9000 Ghent, Belgium. Sofie.Lust@ugent.be
Sofie
S
Lust
Barbara
B
Vanhoecke
Mireille
M
VAN Gele
Jerina
J
Boelens
Heleen
H
VAN Melckebeke
Mary
M
Kaileh
Wim
W
Vanden Berghe
Guy
G
Haegeman
Jan
J
Philippé
Marc
M
Bracke
Fritz
F
Offner
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011427:Propiophenones / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D005419:Flavonoids; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D011427:Propiophenones; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C000717247:HSPA5 protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C403982:ERN2 protein, human; C104536:xanthohumol