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Research ArticleExperimental Studies

Xanthohumol Activates the Proapoptotic Arm of the Unfolded Protein Response in Chronic Lymphocytic Leukemia

SOFIE LUST, BARBARA VANHOECKE, MIREILLE VAN GELE, JERINA BOELENS, HELEEN VAN MELCKEBEKE, MARY KAILEH, WIM VANDEN BERGHE, GUY HAEGEMAN, JAN PHILIPPÉ, MARC BRACKE and FRITZ OFFNER
Anticancer Research October 2009, 29 (10) 3797-3805;
SOFIE LUST
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  • For correspondence: Sofie.Lust@ugent.be
BARBARA VANHOECKE
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MIREILLE VAN GELE
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JERINA BOELENS
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HELEEN VAN MELCKEBEKE
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MARY KAILEH
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WIM VANDEN BERGHE
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GUY HAEGEMAN
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JAN PHILIPPÉ
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MARC BRACKE
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FRITZ OFFNER
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Abstract

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). Patients and 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 (eIF2α), 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. Conclusion: 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.

  • Chronic lymphocytic leukemia
  • ER stress
  • XBP1 splicing
  • apoptosis
  • proteasome
  • Received March 10, 2009.
  • Revision received July 15, 2009.
  • Accepted July 22, 2009.
  • Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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Anticancer Research: 29 (10)
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October 2009
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Xanthohumol Activates the Proapoptotic Arm of the Unfolded Protein Response in Chronic Lymphocytic Leukemia
SOFIE LUST, BARBARA VANHOECKE, MIREILLE VAN GELE, JERINA BOELENS, HELEEN VAN MELCKEBEKE, MARY KAILEH, WIM VANDEN BERGHE, GUY HAEGEMAN, JAN PHILIPPÉ, MARC BRACKE, FRITZ OFFNER
Anticancer Research Oct 2009, 29 (10) 3797-3805;

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Xanthohumol Activates the Proapoptotic Arm of the Unfolded Protein Response in Chronic Lymphocytic Leukemia
SOFIE LUST, BARBARA VANHOECKE, MIREILLE VAN GELE, JERINA BOELENS, HELEEN VAN MELCKEBEKE, MARY KAILEH, WIM VANDEN BERGHE, GUY HAEGEMAN, JAN PHILIPPÉ, MARC BRACKE, FRITZ OFFNER
Anticancer Research Oct 2009, 29 (10) 3797-3805;
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