Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors.
Animals
Antineoplastic Agents
/ pharmacology
Binding Sites
Cell Line, Tumor
Cell Movement
/ drug effects
Cisplatin
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
Female
Humans
Liposomes
Mice
Mice, Nude
MicroRNAs
/ administration & dosage
Mutation, Missense
Neoplasm Invasiveness
/ prevention & control
Ovarian Neoplasms
/ drug therapy
Protein Isoforms
/ genetics
Signal Transduction
/ drug effects
Transcription Factors
/ genetics
Transcriptional Activation
/ genetics
Transfection
Tumor Suppressor Protein p53
/ genetics
Tumor Suppressor Proteins
/ genetics
Xenograft Model Antitumor Assays
3-dimensional (3D) spheroids
B-cell lymphoma 2-like protein 11 (BIM)
chemosensitization
cisplatin
leoyl-sn-glycero-3-phosphatidylcholine (DOPC)
microRNA 130b (miR-130b)
ovarian cancer
transactivation (TA) and N-terminally truncated (ΔN) isoforms of the p63 protein (TAp63/ΔNp63)
tumor protein p53
tumor-targeted nanocomplex (scL)
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
15 07 2019
15 07 2019
Historique:
received:
11
09
2018
revised:
25
11
2018
accepted:
17
12
2018
pubmed:
24
4
2019
medline:
9
4
2020
entrez:
24
4
2019
Statut:
ppublish
Résumé
Over 96% of high-grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer. A novel strategy is presented for circumventing alterations in p53 by inducing the tumor-suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA-130b (miR-130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer. Treatment with miR-130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild-type) and disruption of multicellular spheroids in OVCAR8 cells (p53-mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B-cell lymphoma (Bcl)-inhibitor B-cell lymphoma 2-like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR-130b. In vivo, combined miR-130b plus CDDP exhibited greater therapeutic efficacy than miR-130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR-130b in 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP-treated mice, and 20% of DOPC-miR-130b plus CDDP-treated mice were living tumor free. Systemic injections of scL-miR-130b plus CDDP in a clinically tested, tumor-targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts. The miR-130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad-spectrum therapeutic options for the majority of p53-altered cancers.
Sections du résumé
BACKGROUND
Over 96% of high-grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer.
METHODS
A novel strategy is presented for circumventing alterations in p53 by inducing the tumor-suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA-130b (miR-130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer.
RESULTS
Treatment with miR-130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild-type) and disruption of multicellular spheroids in OVCAR8 cells (p53-mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B-cell lymphoma (Bcl)-inhibitor B-cell lymphoma 2-like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR-130b. In vivo, combined miR-130b plus CDDP exhibited greater therapeutic efficacy than miR-130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR-130b in 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP-treated mice, and 20% of DOPC-miR-130b plus CDDP-treated mice were living tumor free. Systemic injections of scL-miR-130b plus CDDP in a clinically tested, tumor-targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts.
CONCLUSIONS
The miR-130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad-spectrum therapeutic options for the majority of p53-altered cancers.
Identifiants
pubmed: 31012964
doi: 10.1002/cncr.32053
pmc: PMC6617807
doi:
Substances chimiques
Antineoplastic Agents
0
Liposomes
0
MIRN130 microRNA, human
0
MicroRNAs
0
Protein Isoforms
0
TP53 protein, human
0
TP63 protein, human
0
Transcription Factors
0
Tumor Suppressor Protein p53
0
Tumor Suppressor Proteins
0
Cisplatin
Q20Q21Q62J
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
2409-2422Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA160394
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009686
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218025
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197452
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA132012
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK094981
Pays : United States
Informations de copyright
© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
Références
J Pharmacol Exp Ther. 1999 Nov;291(2):865-9
pubmed: 10525110
J Cell Biol. 1999 Nov 15;147(4):823-30
pubmed: 10562283
Oncogene. 2001 Sep 13;20(41):5818-25
pubmed: 11593387
Mol Cancer Ther. 2002 Mar;1(5):337-46
pubmed: 12489850
Ann N Y Acad Sci. 2003 Dec;1002:78-89
pubmed: 14751825
N Engl J Med. 2004 Dec 9;351(24):2519-29
pubmed: 15590954
Cancer Res. 2005 Aug 1;65(15):6910-8
pubmed: 16061675
Mol Cancer Ther. 2006 May;5(5):1239-47
pubmed: 16731756
Nature. 2006 Nov 30;444(7119):624-8
pubmed: 17122775
Nature. 2007 Feb 8;445(7128):661-5
pubmed: 17251932
Cancer Res. 2007 Apr 1;67(7):2938-43
pubmed: 17409398
Cell. 2007 Aug 24;130(4):601-10
pubmed: 17719539
Gynecol Oncol. 2008 Dec;111(3):478-86
pubmed: 18823650
Nat Rev Cancer. 2009 Oct;9(10):701-13
pubmed: 19693097
Nat Med. 2009 Oct;15(10):1179-85
pubmed: 19783996
Nat Cell Biol. 2009 Dec;11(12):1451-7
pubmed: 19898465
PLoS One. 2010 Mar 10;5(3):e9637
pubmed: 20224791
Cold Spring Harb Perspect Biol. 2010 Sep;2(9):a004887
pubmed: 20484388
Cold Spring Harb Perspect Biol. 2010 Jun;2(6):a001198
pubmed: 20516129
Nature. 2010 Oct 21;467(7318):986-90
pubmed: 20962848
Biochem Biophys Res Commun. 2010 Dec 17;403(3-4):310-5
pubmed: 21075072
Stem Cells Dev. 2011 Aug;20(8):1319-26
pubmed: 21142794
Cancer Res. 2011 Feb 1;71(3):1167-76
pubmed: 21266360
J Clin Invest. 2011 Mar;121(3):893-904
pubmed: 21285512
Lancet Oncol. 2011 Apr;12(4):319-21
pubmed: 21463831
Nature. 2011 Jun 29;474(7353):609-15
pubmed: 21720365
Cell Death Differ. 2011 Sep;18(9):1487-99
pubmed: 21760596
Biochim Biophys Acta. 2012 Mar;1820(3):291-317
pubmed: 21851850
Gynecol Oncol. 2012 Feb;124(2):325-34
pubmed: 22005523
Oncogene. 2013 Jul 4;32(27):3286-95
pubmed: 22847613
Mol Ther. 2013 May;21(5):1096-103
pubmed: 23609015
Cancers (Basel). 2011 Mar 15;3(1):1351-71
pubmed: 24212665
Curr Drug Targets. 2014 Jan;15(1):80-9
pubmed: 24387333
PLoS One. 2014 May 09;9(5):e96472
pubmed: 24816756
Mol Med Rep. 2016 Jan;13(1):188-96
pubmed: 26573160
Gene. 2016 Jul 15;586(1):48-55
pubmed: 27048832
Open Biol. 2016 Nov;6(11):
pubmed: 27906134
Sci Rep. 2017 Jun 15;7(1):3614
pubmed: 28620240
Cancer Res. 1995 Nov 1;55(21):5038-42
pubmed: 7585548
Oncogene. 1997 Sep;15(11):1363-7
pubmed: 9315105