title: ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21.
abstract: To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in high-risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy. Among the molecular signatures associated with chemotherapy, transcripts encoding inhibitor of DNA binding 1 (ID1) were significantly upregulated. The patient biochemical relapse status was monitored in a long-term follow-up. Patients with ID1 upregulation were found to be associated with longer relapse-free survival than patients without ID1 increase. This in vivo clinical association was mechanistically investigated. The chemotherapy-induced ID1 upregulation was recapitulated in the prostate cancer cell line LNCaP. Docetaxel dose-dependently induced ID1 transcription, which was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Stable ID1 overexpression in LNCaP increased cell proliferation, promoted G(1) cell cycle progression, and enhanced docetaxel-induced cytotoxicity. These changes were accompanied by a decrease in cellular mitochondria content, an increase in BCL2 phosphorylation at serine 70, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel-induced cytotoxicity by inhibiting cell death. ID1-mediated chemosensitivity enhancement was in part due to ID1 suppression of p21. Overexpression of p21 in LNCaP-ID1-overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These molecular data provide a mechanistic rationale for the observed in vivo clinical association between ID1 upregulation and relapse-free survival. Taken together, it shows that ID1 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon 97239, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Geng
authors.forename: Brooks L
authors.initials: BL
authors.lastname: Rademacher
authors.forename: Janet
authors.initials: J
authors.lastname: Pittsenbarger
authors.forename: Chung-Ying
authors.initials: CY
authors.lastname: Huang
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Harvey
authors.forename: Marie C
authors.initials: MC
authors.lastname: Lafortune
authors.forename: Anne
authors.initials: A
authors.lastname: Myrthue
authors.forename: Mark
authors.initials: M
authors.lastname: Garzotto
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: David Z
authors.initials: DZ
authors.lastname: Qian
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D016271:Proto-Oncogene Proteins c-myc; D043823:Taxoids; D000077143:Docetaxel; D011065:Poly(ADP-ribose) Polymerases
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19506-11
references.pmid: 18048329
references.citation: Mol Cell Biol. 2007 May;27(9):3530-41
references.pmid: 17325029
references.citation: Nature. 2005 Jul 28;436(7050):518-24
references.pmid: 16049480
references.citation: Oncogene. 2001 Dec 20;20(58):8334-41
references.pmid: 11840326
references.citation: PLoS One. 2007 Dec 19;2(12):e1338
references.pmid: 18092003
references.citation: J Biol Chem. 2007 Nov 16;282(46):33284-33294
references.pmid: 17855368
references.citation: J Clin Oncol. 2006 Aug 10;24(23):3763-70
references.pmid: 16822846
references.citation: Urol Oncol. 2006 May-Jun;24(3):254-9
references.pmid: 16678060
references.citation: Mol Cell Biol. 2007 Nov;27(21):7381-93
references.pmid: 17785433
references.citation: Oncogene. 2001 Dec 20;20(58):8326-33
references.pmid: 11840325
references.citation: Int J Cancer. 2006 Apr 15;118(8):2072-81
references.pmid: 16287090
references.citation: J Clin Oncol. 2008 Jan 10;26(2):242-5
references.pmid: 18182665
references.citation: J Virol. 2004 Dec;78(24):13470-8
references.pmid: 15564458
references.citation: J Biol Chem. 1994 Jan 21;269(3):2139-45
references.pmid: 8294468
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1308-14
references.pmid: 17317842
references.citation: Cancer Res. 1995 Nov 15;55(22):5187-90
references.pmid: 7585571
references.citation: J Urol. 2002 Jun;167(6):2598-602
references.pmid: 11992094
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7812-6
references.pmid: 11427735
references.citation: J Biol Chem. 1998 Feb 27;273(9):4928-36
references.pmid: 9478937
references.citation: Clin Cancer Res. 2004 Mar 15;10(6):2044-51
references.pmid: 15041724
references.citation: Oncogene. 2005 Jan 13;24(3):381-9
references.pmid: 15489884
references.citation: Clin Cancer Res. 2007 Oct 1;13(19):5825-33
references.pmid: 17908975
references.citation: Science. 1998 Nov 20;282(5393):1497-501
references.pmid: 9822382
references.citation: Cancer Cell. 2003 Oct;4(4):291-9
references.pmid: 14585356
references.citation: Cancer Res. 2006 Nov 15;66(22):10870-7
references.pmid: 17108123
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3562-70
references.pmid: 18519790
references.citation: Clin Cancer Res. 2005 Jul 15;11(14):5233-40
references.pmid: 16033841
references.citation: Cancer Chemother Pharmacol. 2007 Aug;60(3):329-39
references.pmid: 17256134
references.citation: Biol Cell. 2006 Sep;98(9):523-33
references.pmid: 16686600
references.citation: Int J Cancer. 2006 Sep 1;119(5):1164-75
references.pmid: 16557594
references.citation: J Biol Chem. 1998 Oct 2;273(40):25922-8
references.pmid: 9748268
references.citation: Nat Med. 2001 Nov;7(11):1194-201
references.pmid: 11689883
references.citation: J Urol. 2005 Nov;174(5):2022-6
references.pmid: 16217386
references.citation: Oncogene. 2002 Dec 5;21(55):8498-505
references.pmid: 12466969
references.citation: Cancer Cell. 2003 Jun;3(6):525-30
references.pmid: 12842081
references.citation: Nat Clin Pract Urol. 2005 Feb;2(2):92-100; quiz 1 p following 112
references.pmid: 16474654
references.citation: Cancer. 2007 Sep 15;110(6):1248-54
references.pmid: 17674353
references.citation: Mol Cell Biol. 1999 Dec;19(12):8240-53
references.pmid: 10567549
references.citation: Int J Oncol. 1998 Oct;13(4):659-64
references.pmid: 9735392
references.citation: Nature. 2002 Oct 17;419(6908):729-34
references.pmid: 12384701
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17834-9
references.pmid: 17093053
references.citation: Carcinogenesis. 2004 Apr;25(4):517-25
references.pmid: 14688027
references.citation: Cancer Res. 2008 Apr 15;68(8):3026-36
references.pmid: 18413773
references.citation: N Engl J Med. 2004 Oct 7;351(15):1502-12
references.pmid: 15470213
references.citation: Cancer Res. 2004 Sep 15;64(18):6626-34
references.pmid: 15374977
references.citation: Oncogene. 2003 Jul 17;22(29):4498-508
references.pmid: 12881706
references.citation: Prostate. 2007 Aug 1;67(11):1182-93
references.pmid: 17520666
references.citation: J Clin Invest. 1999 Aug;104(3):263-9
references.pmid: 10430607
references.citation: J Biol Chem. 2001 Oct 19;276(42):39213-9
references.pmid: 11498533
references.citation: Clin Cancer Res. 2009 May 1;15(9):3135-42
references.pmid: 19366833