title: Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors.
abstract: Burkitt lymphoma is characterized by deregulation of c-myc, and therapies targeting c-myc are under investigation as treatments. Histone deacetylase inhibitors are known to abrogate c-myc expression, leading us to examine their effect in a series of Burkitt lymphoma cell lines. While treatment with romidepsin, panobinostat, vorinostat, or belinostat for 48 h resulted in complete cell death in the Ramos and ST486 lines, CA46 and DG75 cells were resistant. In parallel studies, CA46 and DG75 cells were also insensitive to 48 h treatment with the Aurora kinase inhibitors (AKIs) MLN8237 (alisertib), VX-680 (tozasertib), or ZM447439. Bax knockdown is known to lead to HDI resistance, and we found that loss of Bax or both Bak and Bax correlated with resistance to both AKIs and HDIs in the Burkitt cell lines. As proof-of-concept to evaluate the contribution of Bax and Bak to HDI-mediated apoptosis, we found that apoptosis was unaffected in HCT-116 colon carcinoma cells lacking Bak, blunted in cells lacking Bax, and nearly completely abrogated in cells lacking both Bak and Bax compared with wild-type cells. To explore potential clinical variations in Bak and Bax expression, a series of samples from 16 patients diagnosed with Burkitt lymphoma was examined. While the majority of samples were positive for both Bak and Bax, some (3/16) expressed low levels of both proteins. We thus conclude that HDI-mediated and AKI-mediated apoptosis requires mitochondrial engagement, and that baseline Bax and Bak expression may serve as biomarkers for patients with Burkitt lymphoma likely to respond to HDI treatment.
authors: Medical Oncology Branch; National Cancer Institute; Bethesda, MD USA.
authors: Caterina
authors: C
authors: Ierano
authors: Arup R
authors: AR
authors: Chakraborty
authors: Alina
authors: A
authors: Nicolae
authors: Julian C
authors: JC
authors: Bahr
authors: Zhirong
authors: Z
authors: Zhan
authors: Stefania
authors: S
authors: Pittaluga
authors: Susan E
authors: SE
authors: Bates
authors: Robert W
authors: RW
authors: Robey
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D047630:Depsipeptides / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000172:deficiency* / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C087123:romidepsin; D064127:Aurora Kinases
keywords: Bak; Bax; histone deacetylase inhibitor; romidepsin; vorinostat
references: Leuk Lymphoma. 2004 Apr;45(4):761-7
references: 15160953
references: Adv Hematol. 2012;2012:130680
references: 22287968
references: Oncotarget. 2012 Jan;3(1):31-43
references: 22289787
references: Transplantation. 2002 Jan 27;73(2):271-9
references: 11821743
references: Oncogene. 2012 Jun 28;31(26):3177-89
references: 22056880
references: Clin Cancer Res. 2009 Jun 15;15(12):3947-57
references: 19509170
references: Nat Immunol. 2012 Nov;13(11):1092-100
references: 23001146
references: Arch Surg. 2009 Aug;144(8):722-7
references: 19687375
references: Cancer Res. 1995 Oct 1;55(19):4471-8
references: 7671262
references: Blood. 2013 May 16;121(20):4115-25
references: 23532732
references: Clin Cancer Res. 2007 Jul 15;13(14):4146-53
references: 17634542
references: J Clin Oncol. 2011 Mar 20;29(9):1198-203
references: 21300924
references: Oncogene. 1999 Nov 25;18(50):7016-25
references: 10597302
references: Blood. 2003 Jul 15;102(2):652-8
references: 12649137
references: Mol Pharm. 2011 Dec 5;8(6):2021-31
references: 21899343
references: J Natl Cancer Inst. 2002 Apr 3;94(7):504-13
references: 11929951
references: Biochem Pharmacol. 2011 May 1;81(9):1106-15
references: 21371446
references: Biochem Pharmacol. 2002 Oct 1;64(7):1079-90
references: 12234611
references: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10872-7
references: 10984511
references: Science. 2001 Apr 27;292(5517):727-30
references: 11326099
references: Expert Rev Gastroenterol Hepatol. 2011 Jun;5(3):385-99
references: 21651356
references: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11317-22
references: 18685088
references: Oncotarget. 2012 Oct;3(10):1066-7
references: 23164662
references: Mol Cancer Ther. 2008 May;7(5):1066-79
references: 18483296
references: Clin Cancer Res. 2006 Aug 1;12(15):4628-35
references: 16899611
references: Blood. 2011 Jun 2;117(22):5827-34
references: 21355097
references: Oncotarget. 2012 Nov;3(11):1416-27
references: 23232026
references: Science. 1997 Feb 14;275(5302):967-9
references: 9020077
references: Clin Cancer Res. 1998 Apr;4(4):1071-4
references: 9563904
references: J Clin Oncol. 2012 Feb 20;30(6):631-6
references: 22271479
references: Clin Cancer Res. 2006 Mar 1;12(5):1547-55
references: 16533780
references: Dig Dis Sci. 2011 Jan;56(1):131-8
references: 20503071
references: Br J Haematol. 2000 Oct;111(1):182-9
references: 11091199
references: Blood. 2004 Jun 15;103(12):4636-43
references: 14996704
references: Clin Cancer Res. 2002 Mar;8(3):718-28
references: 11895901
references: J Pharmacol Exp Ther. 2005 Jul;314(1):467-75
references: 15833893
references: Science. 2000 Nov 3;290(5493):989-92
references: 11062132
references: Cancer Res. 1999 Feb 1;59(3):696-703
references: 9973220
references: Br J Cancer. 2003 Feb 24;88(4):586-92
references: 12592374
references: Oncogene. 1998 Jul 16;17(2):157-63
references: 9674699
references: Cell Death Differ. 2012 Dec;19(12):2029-39
references: 22858545
references: Biochem Pharmacol. 2010 Jan 15;79(2):122-9
references: 19686703
references: Biosci Biotechnol Biochem. 1994 Sep;58(9):1579-83
references: 7765477
references: J Clin Oncol. 2010 Oct 10;28(29):4485-91
references: 20697094
references: Proc Natl Acad Sci U S A. 2007 May 8;104(19):8071-6
references: 17470784
references: Lancet Oncol. 2011 Dec;12(13):1222-8
references: 22033282
references: Int J Cancer. 2010 Nov 1;127(9):2199-208
references: 20127862
references: J Clin Oncol. 2007 Jul 20;25(21):3109-15
references: 17577020
references: Cancer Res. 2002 Jul 15;62(14):4095-9
references: 12124347
references: Br J Haematol. 2012 Mar;156(6):744-56
references: 22260300
references: J Clin Oncol. 2009 Nov 10;27(32):5410-7
references: 19826128
references: Leuk Res. 2009 Jul;33(7):929-36
references: 19233470
references: Lab Invest. 2009 Dec;89(12):1364-73
references: 19823168
references: Future Med Chem. 2012 Mar;4(4):505-24
references: 22416777
references: PLoS One. 2010 Jun 03;5(6):e10941
references: 20532179
references: Oncogene. 1998 Apr 9;16(14):1803-12
references: 9583678
references: Oncogene. 1998 Sep 24;17(12):1503-8
references: 9794227