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

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Xanthohumol Activates the Proapoptotic Arm of the Unfolded Protein Response in

Chronic Lymphocytic Leukemia

1.. SOFIE LUST1,2,

2.. BARBARA VANHOECKE2,

3.. MIREILLE VAN GELE3,

4.. JERINA BOELENS1,

5.. HELEEN VAN MELCKEBEKE1,

6.. MARY KAILEH4,

7.. WIM VANDEN BERGHE4,

8.. GUY HAEGEMAN4,

9.. JAN PHILIPPÉ5,

10.. MARC BRACKE2 and

11.. FRITZ OFFNER1

+ Author Affiliations

1.. 1Department of Hematology, Ghent University Hospital, De Pintelaan 185,

9000 Ghent

2.. 2Laboratory of Experimental Cancer Research, Department of Radiotherapy

and Nuclear Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent

3.. 3Department of Dermatology, Ghent University Hospital, De Pintelaan 185,

9000 Ghent

4.. 4Laboratory of Eukaryotic Gene Expression and Signal Transduction

(LEGEST), Department of Molecular Biology, Ghent University, K.L.

Ledeganckstraat 35, 9000 Ghent, Belgium

5.. 5Department of Clinical Chemistry, Microbiology and Immunology, Ghent

University Hospital, De Pintelaan 185, 9000 Ghent

1.. Correspondence to: Sofie Lust, Ghent University Hospital, Department of

Hematology, De Pintelaan 185, 1P7, B-9000 Ghent, Belgium, Tel: +32 093323909,

Fax: +32 093324991, e-mail: Sofie.Lust@...

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 (eIF2?), 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.

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