Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 04 2021
01 04 2021
Historique:
received:
11
11
2020
revised:
22
12
2020
accepted:
19
01
2021
pubmed:
27
1
2021
medline:
11
3
2022
entrez:
26
1
2021
Statut:
ppublish
Résumé
Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells. We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development. The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells. Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.
Identifiants
pubmed: 33495313
pii: 1078-0432.CCR-20-4391
doi: 10.1158/1078-0432.CCR-20-4391
pmc: PMC8026555
mid: NIHMS1667658
doi:
Substances chimiques
CREB1 protein, human
0
Cyclic AMP Response Element-Binding Protein
0
p300-CBP Transcription Factors
EC 2.3.1.48
Abiraterone Acetate
EM5OCB9YJ6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2087-2099Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
Références
Oncol Rep. 2007 Oct;18(4):953-8
pubmed: 17786359
Bioinformatics. 2017 Aug 01;33(15):2413-2415
pubmed: 28379339
Expert Rev Anticancer Ther. 2018 Sep;18(9):823-836
pubmed: 30101644
Cell Death Dis. 2019 May 28;10(6):405
pubmed: 31138777
Cancer Discov. 2014 Oct;4(10):1230-41
pubmed: 25084773
Pharmacol Res Perspect. 2015 Jun;3(3):e00149
pubmed: 26171228
Clin Cancer Res. 2011 Sep 15;17(18):5913-25
pubmed: 21807635
N Engl J Med. 2013 Jan 10;368(2):138-48
pubmed: 23228172
J Clin Oncol. 2016 Jun 20;34(18):2098-106
pubmed: 26811535
Clin Cancer Res. 2009 May 15;15(10):3251-5
pubmed: 19447877
Nature. 2015 Jul 16;523(7560):347-51
pubmed: 26030522
Cancer. 2008 Mar 15;112(6):1247-53
pubmed: 18293426
Endocr Rev. 2004 Apr;25(2):276-308
pubmed: 15082523
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10
pubmed: 16381825
Nat Biotechnol. 2016 Apr;34(4):419-23
pubmed: 26928769
Prostate. 2019 Jun;79(9):937-948
pubmed: 31017696
J Mol Cell Cardiol. 2016 Dec;101:1-10
pubmed: 27789289
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Genome Biol. 2014;15(12):550
pubmed: 25516281
Int J Cancer. 2019 Sep 1;145(5):1382-1394
pubmed: 30828788
Nucleic Acids Res. 2000 Jan 1;28(1):316-9
pubmed: 10592259
J Clin Oncol. 2018 Sep 1;36(25):2639-2646
pubmed: 30028657
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4459-64
pubmed: 15753290
Oncol Rep. 2017 Jun;37(6):3361-3368
pubmed: 28498439
Oncogene. 2007 Aug 2;26(35):5070-7
pubmed: 17310988
J Clin Oncol. 2014 Nov 20;32(33):3705-15
pubmed: 25311217
J Biol Chem. 2009 Jun 5;284(23):15390-9
pubmed: 19324884
CA Cancer J Clin. 1972 Jul-Aug;22(4):232-40
pubmed: 4625049
Graefes Arch Clin Exp Ophthalmol. 2019 Oct;257(10):2329-2341
pubmed: 31309275
Oncogene. 2014 May 29;33(22):2815-25
pubmed: 23752196
Cell. 2013 Aug 29;154(5):1074-1084
pubmed: 23993097
Nat Commun. 2018 Oct 4;9(1):4080
pubmed: 30287808
Hum Pathol. 2015 Feb;46(2):231-8
pubmed: 25476123
Cancer Res. 2011 Oct 15;71(20):6503-13
pubmed: 21868758
Nucleic Acids Res. 2017 Jun 20;45(11):6993
pubmed: 28419278
N Engl J Med. 2014 Sep 11;371(11):1028-38
pubmed: 25184630
Horm Cancer. 2014 Apr;5(2):72-89
pubmed: 24615402
J Cell Biochem. 2012 Nov;113(11):3587-98
pubmed: 22740515
J Clin Med. 2019 Mar 13;8(3):
pubmed: 30871130
BMC Cancer. 2019 May 23;19(1):487
pubmed: 31122212
Clin Cancer Res. 2014 Mar 15;20(6):1590-600
pubmed: 24449822
Pharmacol Rev. 2006 Sep;58(3):621-81
pubmed: 16968952
Lancet Oncol. 2012 Oct;13(10):983-92
pubmed: 22995653
Acta Pharmacol Sin. 2015 Jan;36(1):3-23
pubmed: 24909511
J Cell Biochem. 2006 Oct 1;99(2):362-72
pubmed: 16619264
Am J Pathol. 2009 Nov;175(5):2197-206
pubmed: 19815709
J Biol Chem. 2014 Jan 31;289(5):2711-24
pubmed: 24338025
Gen Comp Endocrinol. 2011 Dec 1;174(3):309-17
pubmed: 21963961