ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21.
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.
Geng
Hao
H
Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Rademacher
Brooks L
BL
Pittsenbarger
Janet
J
Huang
Chung-Ying
CY
Harvey
Christopher T
CT
Lafortune
Marie C
MC
Myrthue
Anne
A
Garzotto
Mark
M
Nelson
Peter S
PS
Beer
Tomasz M
TM
Qian
David Z
DZ
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*
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
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19506-11
18048329
Mol Cell Biol. 2007 May;27(9):3530-41
17325029
Nature. 2005 Jul 28;436(7050):518-24
16049480
Oncogene. 2001 Dec 20;20(58):8334-41
11840326
PLoS One. 2007 Dec 19;2(12):e1338
18092003
J Biol Chem. 2007 Nov 16;282(46):33284-33294
17855368
J Clin Oncol. 2006 Aug 10;24(23):3763-70
16822846
Urol Oncol. 2006 May-Jun;24(3):254-9
16678060
Mol Cell Biol. 2007 Nov;27(21):7381-93
17785433
Oncogene. 2001 Dec 20;20(58):8326-33
11840325
Int J Cancer. 2006 Apr 15;118(8):2072-81
16287090
J Clin Oncol. 2008 Jan 10;26(2):242-5
18182665
J Virol. 2004 Dec;78(24):13470-8
15564458
J Biol Chem. 1994 Jan 21;269(3):2139-45
8294468
Clin Cancer Res. 2007 Feb 15;13(4):1308-14
17317842
Cancer Res. 1995 Nov 15;55(22):5187-90
7585571
J Urol. 2002 Jun;167(6):2598-602
11992094
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7812-6
11427735
J Biol Chem. 1998 Feb 27;273(9):4928-36
9478937
Clin Cancer Res. 2004 Mar 15;10(6):2044-51
15041724
Oncogene. 2005 Jan 13;24(3):381-9
15489884
Clin Cancer Res. 2007 Oct 1;13(19):5825-33
17908975
Science. 1998 Nov 20;282(5393):1497-501
9822382
Cancer Cell. 2003 Oct;4(4):291-9
14585356
Cancer Res. 2006 Nov 15;66(22):10870-7
17108123
Clin Cancer Res. 2008 Jun 1;14(11):3562-70
18519790
Clin Cancer Res. 2005 Jul 15;11(14):5233-40
16033841
Cancer Chemother Pharmacol. 2007 Aug;60(3):329-39
17256134
Biol Cell. 2006 Sep;98(9):523-33
16686600
Int J Cancer. 2006 Sep 1;119(5):1164-75
16557594
J Biol Chem. 1998 Oct 2;273(40):25922-8
9748268
Nat Med. 2001 Nov;7(11):1194-201
11689883
J Urol. 2005 Nov;174(5):2022-6
16217386
Oncogene. 2002 Dec 5;21(55):8498-505
12466969
Cancer Cell. 2003 Jun;3(6):525-30
12842081
Nat Clin Pract Urol. 2005 Feb;2(2):92-100; quiz 1 p following 112
16474654
Cancer. 2007 Sep 15;110(6):1248-54
17674353
Mol Cell Biol. 1999 Dec;19(12):8240-53
10567549
Int J Oncol. 1998 Oct;13(4):659-64
9735392
Nature. 2002 Oct 17;419(6908):729-34
12384701
Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17834-9
17093053
Carcinogenesis. 2004 Apr;25(4):517-25
14688027
Cancer Res. 2008 Apr 15;68(8):3026-36
18413773
N Engl J Med. 2004 Oct 7;351(15):1502-12
15470213
Cancer Res. 2004 Sep 15;64(18):6626-34
15374977
Oncogene. 2003 Jul 17;22(29):4498-508
12881706
Prostate. 2007 Aug 1;67(11):1182-93
17520666
J Clin Invest. 1999 Aug;104(3):263-9
10430607
J Biol Chem. 2001 Oct 19;276(42):39213-9
11498533
Clin Cancer Res. 2009 May 1;15(9):3135-42
19366833