title: Regulation of OSU-03012 toxicity by ER stress proteins and ER stress-inducing drugs.
abstract: The present studies examined the toxic interaction between the non-coxib celecoxib derivative OSU-03012 and phosphodiesterase 5 (PDE5) inhibitors, and also determined the roles of endoplasmic reticulum stress response regulators in cell survival. PDE5 inhibitors interacted in a greater than additive fashion with OSU-03012 to kill parental glioma and stem-like glioma cells. Knockdown of the endoplasmic reticulum stress response proteins IRE1 or XBP1 enhanced the lethality of OSU-03012, and of [OSU-03012 + PDE5 inhibitor] treatment. Pan-caspase and caspase-9 inhibition did not alter OSU-03012 lethality but did abolish enhanced killing in the absence of IRE1 or XBP1. Expression of the mitochondrial protective protein BCL-XL or the caspase-8 inhibitor c-FLIP-s, or knockdown of death receptor CD95 or the death receptor caspase-8 linker protein FADD, suppressed killing by [OSU-03012 + PDE5 inhibitor] treatment. CD95 activation was blocked by the nitric oxide synthase inhibitor L-NAME. Knockdown of the autophagy regulatory proteins Beclin1 or ATG5 protected the cells from OSU-03012 and from [OSU-03012 + PDE5 inhibitor] toxicity. Knockdown of IRE1 enhanced OSU-03012/[OSU-03012 + PDE5 inhibitor]-induced JNK activation, and inhibition of JNK suppressed the elevated killing caused by IRE1 knockdown. Knockdown of CD95 blunted JNK activation. Collectively, our data demonstrate that PDE5 inhibitors recruit death receptor signaling to enhance OSU-03012 toxicity in glioblastoma multiforme (GBM) cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia. pdent@vcu.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D002243:Carbolines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology*; D000068581:Tadalafil; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D000071717:X-Box Binding Protein 1
chemical_list: D002243:Carbolines; D004268:DNA-Binding Proteins; C500894:OSU 03012; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D000071701:Regulatory Factor X Transcription Factors; D013449:Sulfonamides; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D000068581:Tadalafil; D000068677:Sildenafil Citrate; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
references.citation: Science. 2006 Jul 7;313(5783):104-7
references.pmid: 16825573
references.citation: Neuro Oncol. 2005 Apr;7(2):164-76
references.pmid: 15831234
references.citation: Clin Cancer Res. 2005 Nov 15;11(22):8213-21
references.pmid: 16299255
references.citation: J Biol Chem. 1999 Nov 26;274(48):34301-9
references.pmid: 10567406
references.citation: Curr Top Med Chem. 2007;7(4):437-54
references.pmid: 17305584
references.citation: Cold Spring Harb Perspect Biol. 2012 Jun 01;4(6):
references.pmid: 22535228
references.citation: Blood. 2003 Jan 1;101(1):265-9
references.pmid: 12393651
references.citation: J Biol Chem. 2004 Mar 12;279(11):10364-73
references.pmid: 14679192
references.citation: Cancer Biol Ther. 2012 Feb 15;13(4):224-36
references.pmid: 22354011
references.citation: Mol Pharmacol. 2014 Mar;85(3):408-19
references.pmid: 24353313
references.citation: Biochim Biophys Acta. 2013 Dec;1833(12):3460-3470
references.pmid: 23850759
references.citation: J Cell Biochem. 2005 Feb 1;94(2):336-50
references.pmid: 15526282
references.citation: Cancer Res. 2004 Feb 15;64(4):1444-51
references.pmid: 14973075
references.citation: Brain Res. 2008 Sep 16;1230:290-302
references.pmid: 18674521
references.citation: J Biol Chem. 1997 Sep 26;272(39):24125-8
references.pmid: 9305857
references.citation: J Biol Chem. 2012 Nov 30;287(49):41342-51
references.pmid: 23066013
references.citation: J Cell Biochem. 2012 Aug;113(8):2738-43
references.pmid: 22441938
references.citation: FASEB J. 2003 Jun;17(9):1036-47
references.pmid: 12773486
references.citation: J Cell Biol. 2009 Aug 10;186(3):323-31
references.pmid: 19651891
references.citation: Cancer Res. 2004 Jun 1;64(11):3966-73
references.pmid: 15173009
references.citation: Clin Cancer Res. 2005 Mar 1;11(5):1999-2007
references.pmid: 15756026
references.citation: Mol Pharmacol. 2008 Apr;73(4):1168-84
references.pmid: 18182481
references.citation: Mol Pharmacol. 2012 Apr;81(4):527-40
references.pmid: 22219388
references.citation: Am J Cardiol. 1999 Mar 4;83(5A):35C-44C
references.pmid: 10078541
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Aug;289(2):L196-206
references.pmid: 15792963
references.citation: Cancer Biol Ther. 2014 Mar 1;15(3):305-16
references.pmid: 24351423
references.citation: PLoS One. 2013 May 16;8(5):e64344
references.pmid: 23696882
references.citation: Biochem Soc Trans. 2005 Aug;33(Pt 4):724-7
references.pmid: 16042585
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5480-5
references.pmid: 10792026
references.citation: Cell Death Differ. 2012 Feb;19(2):310-20
references.pmid: 21779001
references.citation: Trends Cell Biol. 2013 Nov;23(11):547-55
references.pmid: 23880584
references.citation: J Surg Res. 2001 Dec;101(2):183-9
references.pmid: 11735274
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Feb;296(2):L220-8
references.pmid: 19028977
references.citation: Cancer Biol Ther. 2013 Oct 1;14(10):982-96
references.pmid: 24025251
references.citation: Eur J Pharmacol. 2007 Dec 8;576(1-3):151-9
references.pmid: 17698059
references.citation: Cancer Res. 2004 Jun 15;64(12):4309-18
references.pmid: 15205346
references.citation: Nitric Oxide. 2002 Dec;7(4):229-35
references.pmid: 12446171
references.citation: Oncol Rep. 2006 Jan;15(1):7-13
references.pmid: 16328028
references.citation: Cancer Res. 2010 Aug 1;70(15):6313-24
references.pmid: 20631069
references.citation: Cell Growth Differ. 1998 May;9(5):415-22
references.pmid: 9607562
references.citation: Hypertension. 1996 Mar;27(3 Pt 2):823-6
references.pmid: 8613247
references.citation: Cell Signal. 2011 Dec;23(12):1921-6
references.pmid: 21914472
references.citation: Mol Pharmacol. 2006 Aug;70(2):589-603
references.pmid: 16622074
references.citation: Blood. 2005 Mar 15;105(6):2504-9
references.pmid: 15454489
references.citation: Semin Oncol. 2004 Apr;31(2 Suppl 7):12-21
references.pmid: 15252926
references.citation: Circ Heart Fail. 2012 Jan;5(1):79-86
references.pmid: 22135403
references.citation: J Biol Chem. 2008 Oct 24;283(43):29572-85
references.pmid: 18723505
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18202-7
references.pmid: 20884855
references.citation: Cancer Res. 2000 Jul 1;60(13):3338-42
references.pmid: 10910034
references.citation: Nat Chem Biol. 2012 Oct;8(10):831-8
references.pmid: 22922758
references.citation: Mol Cancer Ther. 2005 Feb;4(2):257-70
references.pmid: 15713897
references.citation: Arch Med Res. 2012 Aug;43(6):470-5
references.pmid: 22960860
references.citation: Prostate. 2006 Feb 15;66(3):257-65
references.pmid: 16175586
references.citation: Cancer Biol Ther. 2012 Dec;13(14):1501-11
references.pmid: 22990204
references.citation: BMC Cancer. 2006 Jan 12;6:9
references.pmid: 16409625
references.citation: FEBS Lett. 1993 Nov 15;334(2):149-52
references.pmid: 7693513
references.citation: Nitric Oxide. 2009 Nov-Dec;21(3-4):149-56
references.pmid: 19635579