title: Phosphorylated IκBα predicts poor prognosis in activated B-cell lymphoma and its inhibition with thymoquinone induces apoptosis via ROS release.
abstract: Activated B-cell lymphoma (ABC), one of the three subtypes of Diffuse Large B-cell Lymphoma (DLBCL) has the worst survival rate after upfront chemotherapy and is characterized by constitutively activated NFκB. We therefore studied the role of NFκB In a cohort of clinical DLBCL samples and ABC cell lines. In our clinical tissue microarray cohort of DLBCL samples, p-IκBα was detected in 38.3% of ABC DLBCL and was an independent prognostic marker for poor survival. In vitro, we found that Thymoquinone (TQ), a natural compound isolated from Nigella sativa caused release of ROS in ABC cells. TQ-mediated release of ROS in turn inhibited NFκB activity by dephosphorylating IκBα and decreased translocation of p65 subunit of NFκB in the nuclear compartment in ABC cell lines. This led to inhibition of cell viability and induction of mitochondrial dependent apoptosis in ABC-DLBCL cell lines. Additionally, TQ treatment also caused up-regulation of death receptor 5 (DR5), however, up-regulation of DR5 did not play a role in TQ-induced apoptosis. Finally, combination of sub-optimal doses of TQ and TRAIL induced efficient apoptosis in ABC-DLBCL cell lines. These data show that p-IκBα can be used as a prognostic marker and target for therapy in this aggressive sub-type of DLBCL and TQ may play an important role in the management of DLBCL in the future.
authors.affiliation: Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Prashant P
authors.initials: PP
authors.lastname: Bavi
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D031881:Nigella sativa / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D000072000:NF-KappaB Inhibitor alpha; C003466:thymoquinone
references.citation: Mol Cancer Ther. 2009 Jun;8(6):1515-25
references.pmid: 19509255
references.citation: Am J Gastroenterol. 2009 Jul;104(7):1790-801
references.pmid: 19491830
references.citation: Nature. 2000 Feb 3;403(6769):503-11
references.pmid: 10676951
references.citation: Cancer Res. 2011 Jan 15;71(2):538-49
references.pmid: 21127198
references.citation: Cancer Cell. 2004 Sep;6(3):203-8
references.pmid: 15380510
references.citation: J Pathol. 2011 Jul;224(3):355-66
references.pmid: 21506127
references.citation: Biomed Sci Instrum. 2007;43:378-83
references.pmid: 17487111
references.citation: Cancer Epidemiol Biomarkers Prev. 1997 Jan;6(1):63-9
references.pmid: 8993799
references.citation: Science. 2008 Mar 21;319(5870):1676-9
references.pmid: 18323416
references.citation: Haematologica. 2012 Jul;97(7):1092-100
references.pmid: 22271891
references.citation: Cancer Cell. 2010 Dec 14;18(6):568-79
references.pmid: 21156281
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2013 Jan;157(1):41-53
references.pmid: 23017276
references.citation: Mol Cell Biol. 1999 Sep;19(9):5923-9
references.pmid: 10454539
references.citation: Hum Pathol. 2008 Jun;39(6):885-94
references.pmid: 18400256
references.citation: Curr Drug Targets. 2012 Dec;13(14):1831-41
references.pmid: 23140293
references.citation: J Biol Chem. 2011 Feb 18;286(7):5546-57
references.pmid: 21156789
references.citation: Biochem Biophys Res Commun. 2008 Aug 8;372(4):870-4
references.pmid: 18534188
references.citation: Apoptosis. 2006 Feb;11(2):245-54
references.pmid: 16502262
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Sep;15(9):1708-18
references.pmid: 16985034
references.citation: Blood. 2007 Jul 15;110(2):735-42
references.pmid: 17463171
references.citation: Free Radic Biol Med. 2011 Apr 15;50(8):978-87
references.pmid: 21215312
references.citation: Leuk Lymphoma. 2009 Jul;50(7):1204-13
references.pmid: 19557642
references.citation: Int J Cancer. 2005 Nov 10;117(3):409-17
references.pmid: 15906362
references.citation: Free Radic Biol Med. 2009 Jun 15;46(12):1639-49
references.pmid: 19345731
references.citation: Mol Cell Biol. 2000 Apr;20(8):2687-95
references.pmid: 10733571
references.citation: J Exp Med. 2001 Dec 17;194(12):1861-74
references.pmid: 11748286
references.citation: Antioxid Redox Signal. 2009 Nov;11(11):2851-97
references.pmid: 19432534
references.citation: Adv Enzyme Regul. 1984;22:27-55
references.pmid: 6382953
references.citation: Zhonghua Zhong Liu Za Zhi. 1999 May;21(3):217-9
references.pmid: 11776841
references.citation: Cancer Res. 2009 Jul 1;69(13):5575-83
references.pmid: 19549912
references.citation: Oncogene. 2010 Aug 19;29(33):4658-70
references.pmid: 20562906
references.citation: Int J Biochem Cell Biol. 2006;38(8):1249-53
references.pmid: 16314136
references.citation: PLoS One. 2011;6(9):e24703
references.pmid: 21931821
references.citation: Trends Cell Biol. 2008 Apr;18(4):157-64
references.pmid: 18314333
references.citation: Clin Cancer Res. 2004 Nov 1;10(21):7252-9
references.pmid: 15534099
references.citation: Expert Opin Pharmacother. 2008 Sep;9(13):2247-58
references.pmid: 18710350
references.citation: Biochem Pharmacol. 2004 Sep 15;68(6):1071-80
references.pmid: 15313403
references.citation: Oncogene. 2004 Apr 12;23(16):2950-66
references.pmid: 15077156
references.citation: Cell Death Differ. 2010 Jan;17(1):54-60
references.pmid: 19590513
references.citation: Leukemia. 2008 Sep;22(9):1746-54
references.pmid: 18580954
references.citation: Cancer Res. 2007 Apr 15;67(8):3888-97
references.pmid: 17440103
references.citation: Korean J Urol. 2012 Oct;53(10):665-72
references.pmid: 23136625
references.citation: Cell Prolif. 2010 Apr;43(2):170-83
references.pmid: 20074295
references.citation: Mol Cancer Ther. 2008 Oct;7(10):3318-29
references.pmid: 18852135
references.citation: Blood. 2003 Feb 1;101(3):1053-62
references.pmid: 12393461