title: Endoplasmic reticulum stress plays a pivotal role in cell death mediated by the pan-deacetylase inhibitor panobinostat in human hepatocellular cancer cells.
abstract: Panobinostat, a pan-deacetylase inhibitor, represents a novel therapeutic option for cancer diseases. Besides its ability to block histone deacetylases (HDACs) by promoting histone hyperacetylation, panobinostat interferes with several cell death pathways providing a potential efficacy against tumors. We have previously demonstrated that panobinostat has a potent apoptotic activity in vitro and causes a significant growth delay of hepatocellular carcinoma (HCC) tumor xenografts in nude mice models. Here, we show that treatment with panobinostat is able to induce noncanonical apoptotic cell death in HepG2 and in Hep3B cells, involving the endoplasmic reticulum (ER) stress by up-regulation of the molecular chaperone binding immunoglobulin protein/glucose-regulated protein 78, activation of eukaryotic initiation factor 2α-activating transcription factor 4 (tax-responsive enhancer element B67) and inositol requiring 1α-X-box binding protein 1 factors, strong increase and nuclear translocation of the transcription factor C/EBP homologous protein/growth arrest and DNA damage-inducible gene 153, and involvement of c-Jun N-terminal kinase. These signaling cascades culminate into the activation of the ER-located caspase-4/12 and of executioner caspases, which finally lead to cell demise. Our results clearly show that panobinostat induces an alternative ER stress-mediated cell death pathway in HCC cells, independent of the p53 status.
authors.affiliation: Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: Montalbano
authors.forename: Petra
authors.initials: P
authors.lastname: Waldegger
authors.forename: Karl
authors.initials: K
authors.lastname: Quint
authors.forename: Samir
authors.initials: S
authors.lastname: Jabari
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Romana
authors.initials: R
authors.lastname: Illig
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Fazio
references.citation: Biochem Biophys Res Commun. 2008 Mar 7;367(2):271-6
references.pmid: 18164684
references.citation: Mol Cancer Ther. 2010 Apr;9(4):942-52
references.pmid: 20371724
references.citation: Autophagy. 2010 Nov;6(8):1057-65
references.pmid: 20962572
references.citation: Acta Pharmacol Sin. 2005 Sep;26(9):1025-33
references.pmid: 16115366
references.citation: Cell Oncol. 2010 Jan 1;32(4):285-300
references.pmid: 20208142
references.citation: Oncol Rep. 2012 Jan;27(1):10-6
references.pmid: 21971930
references.citation: Ann N Y Acad Sci. 2003 Dec;1010:186-94
references.pmid: 15033718
references.citation: Mol Cancer Ther. 2012 Apr;11(4):973-83
references.pmid: 22367781
references.citation: J Pathol. 2010 Jul;221(3):264-74
references.pmid: 20527020
references.citation: Pharmacol Ther. 2012 Jun;134(3):306-16
references.pmid: 22387231
references.citation: Exp Diabetes Res. 2012;2012:589589
references.pmid: 22216020
references.citation: Neurobiol Dis. 2011 Mar;41(3):695-705
references.pmid: 21168498
references.citation: Mol Cell. 2007 Jul 6;27(1):53-66
references.pmid: 17612490
references.citation: J Biomed Biotechnol. 2011;2011:514261
references.pmid: 21765634
references.citation: Nat Rev Mol Cell Biol. 2012 Jan 18;13(2):89-102
references.pmid: 22251901
references.citation: Immunol Cell Biol. 2012 Jan;90(1):85-94
references.pmid: 22124371
references.citation: Curr Pharm Biotechnol. 2012 Sep;13(11):2228-34
references.pmid: 21605076
references.citation: Neoplasia. 2010 Jan;12(1):80-6
references.pmid: 20072656
references.citation: Cancer Res. 2007 Apr 15;67(8):3496-9
references.pmid: 17440054
references.citation: Nat Cell Biol. 2011 Mar;13(3):184-90
references.pmid: 21364565
references.citation: J Immunol Methods. 2005 Jun;301(1-2):102-13
references.pmid: 15982663
references.citation: PLoS One. 2012;7(2):e31518
references.pmid: 22359598
references.citation: Cell Death Differ. 2007 Jan;14(1):44-55
references.pmid: 17053807
references.citation: Cancer Sci. 2006 Aug;97(8):683-8
references.pmid: 16863502
references.citation: Biotechnol Bioeng. 2011 Dec;108(12):2777-93
references.pmid: 21809331
references.citation: Cancer Chemother Pharmacol. 2009 Nov;64(6):1115-22
references.pmid: 19280190
references.citation: Diabetes Obes Metab. 2010 Oct;12 Suppl 2:108-15
references.pmid: 21029307
references.citation: J Hematol Oncol. 2010 Feb 04;3:5
references.pmid: 20132536
references.citation: J Biochem Mol Biol. 2007 Jan 31;40(1):1-6
references.pmid: 17244475
references.citation: Cancer Lett. 2009 Aug 8;280(2):233-41
references.pmid: 19344997
references.citation: Cell Mol Life Sci. 2013 Jul;70(14):2425-41
references.pmid: 23052213
references.citation: Cell Mol Life Sci. 2009 Sep;66(17):2835-50
references.pmid: 19468685
references.citation: World J Gastroenterol. 2012 Feb 14;18(6):498-506
references.pmid: 22363115
references.citation: World J Biol Chem. 2010 May 26;1(5):55-61
references.pmid: 21540990
references.citation: J Hepatol. 2011 Apr;54(4):795-809
references.pmid: 21145844
references.citation: Hematology. 2012 Apr;17 Suppl 1:S105-8
references.pmid: 22507794
references.citation: Cell Death Differ. 2007 Aug;14(8):1467-74
references.pmid: 17464326
references.citation: FEBS Lett. 2007 Jul 31;581(19):3641-51
references.pmid: 17481612
references.citation: Exp Oncol. 2012 Oct;34(3):286-97
references.pmid: 23070014
references.citation: Int J Mol Med. 2009 Jul;24(1):45-50
references.pmid: 19513533
references.citation: Free Radic Res. 2011 Jun;45(6):692-8
references.pmid: 21417786
references.citation: J Cancer. 2012;3:158-65
references.pmid: 22514558
references.citation: Science. 2011 Nov 25;334(6059):1081-6
references.pmid: 22116877
references.citation: Blood. 2012 Feb 2;119(5):1162-72
references.pmid: 22096249
references.citation: J Chem Neuroanat. 2004 Sep;28(1-2):101-5
references.pmid: 15363495
references.citation: J Cell Biol. 2011 Mar 21;192(6):919-27
references.pmid: 21402790
references.citation: J Immunol. 2011 Feb 1;186(3):1564-74
references.pmid: 21191072
references.citation: Adv Exp Med Biol. 2012;738:153-68
references.pmid: 22399379
references.citation: Cancer Res. 2007 Feb 15;67(4):1783-92
references.pmid: 17308121
references.citation: J Biol Chem. 2011 Dec 2;286(48):41862-41870
references.pmid: 22002058
references.citation: Future Oncol. 2009 Jun;5(5):601-12
references.pmid: 19519200
references.citation: Trends Cell Biol. 2004 Jan;14(1):20-8
references.pmid: 14729177
references.citation: Dev Cell. 2011 Sep 13;21(3):492-505
references.pmid: 21920315
references.citation: Cell Death Differ. 2004 Apr;11(4):381-9
references.pmid: 14685163
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Trends Biochem Sci. 2011 Jun;36(6):329-37
references.pmid: 21482118
references.citation: Mol Cell. 2009 Sep 11;35(5):551-61
references.pmid: 19748352
references.citation: Antioxid Redox Signal. 2007 Dec;9(12):2323-33
references.pmid: 17979529
references.citation: J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:213-9
references.pmid: 21199533
references.citation: Exp Cell Res. 2012 Sep 10;318(15):1832-43
references.pmid: 22683924
references.citation: Development. 2008 Nov;135(21):3587-97
references.pmid: 18832389
references.citation: Int J Biochem Cell Biol. 2007;39(7-8):1367-74
references.pmid: 17412634
references.citation: Apoptosis. 2012 Dec;17(12):1300-15
references.pmid: 23011180
references.citation: J Biophys Biochem Cytol. 1958 May 25;4(3):233-42
references.pmid: 13549493
references.citation: Anticancer Res. 2012 Apr;32(4):1379-86
references.pmid: 22493374