Targeting of lactate dehydrogenase C dysregulates the cell cycle and sensitizes breast cancer cells to DNA damage response targeted therapy.
DNA damage
LDHC
cancer testis antigen
cisplatin
olaparib
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
21
04
2021
received:
11
03
2021
accepted:
27
05
2021
pubmed:
30
5
2021
medline:
8
4
2022
entrez:
29
5
2021
Statut:
ppublish
Résumé
The cancer testis antigen (CTA) lactate dehydrogenase C (LDHC) is a promising anticancer target with tumor-specific expression and immunogenicity. Interrogation of breast cancer patient cohorts from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) indicate that upregulation of LDHC expression correlates with unfavorable prognosis. Although the role of LDHC is well characterized in spermatocytes, its role in tumors remains largely unknown. We investigated whether LDHC is involved in regulating genomic stability and whether it could be targeted to affect tumor cellular fitness. Silencing LDHC in four breast cancer cell lines significantly increased the presence of giant cells, nuclear aberrations, DNA damage, and apoptosis. LDHC-silenced cells demonstrated aberrant cell cycle progression with differential expression of cell cycle checkpoint and DNA damage response regulators. In addition, LDHC silencing-induced microtubule destabilization, culminating in increased mitotic catastrophe and reduced long-term survival. Notably, the clonogenicity of LDHC-silenced cells was further reduced by treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and with the DNA-damaging drug cisplatin. This study supports the therapeutic potential of targeting LDHC to mitigate cancer cell survival and improve sensitivity to agents that cause DNA damage or inhibit its repair.
Identifiants
pubmed: 34050611
doi: 10.1002/1878-0261.13024
pmc: PMC8847988
doi:
Substances chimiques
Isoenzymes
0
Phthalazines
0
L-Lactate Dehydrogenase
EC 1.1.1.27
lactate dehydrogenase C4
EC 1.1.1.27.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
885-903Informations de copyright
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
J Exp Clin Cancer Res. 2018 Feb 15;37(1):30
pubmed: 29448954
Clin Chim Acta. 2020 Apr;503:203-209
pubmed: 31794764
Curr Biol. 2006 Jun 20;16(12):1194-200
pubmed: 16782009
Cancer J. 2010 Jan-Feb;16(1):12-6
pubmed: 20164685
Cell Death Dis. 2019 Apr 5;10(4):314
pubmed: 30952840
J Cell Sci. 2018 Apr 12;131(7):
pubmed: 29555820
Genes Dev. 2017 Jan 15;31(2):101-126
pubmed: 28202539
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2754-9
pubmed: 21697511
J Breast Cancer. 2016 Sep;19(3):223-230
pubmed: 27721871
J Transl Med. 2019 Jan 3;17(1):9
pubmed: 30602372
Oncol Lett. 2018 Apr;15(4):5131-5136
pubmed: 29552147
Cancer Res. 2017 Nov 1;77(21):5712-5716
pubmed: 29061671
J Cell Sci. 1998 Mar;111 ( Pt 5):557-72
pubmed: 9454730
Curr Biol. 2017 Dec 4;27(23):R1287-R1292
pubmed: 29207274
Cancers (Basel). 2019 May 29;11(6):
pubmed: 31146503
Biol Reprod. 2008 Jul;79(1):26-34
pubmed: 18367675
Mol Cell Biol. 2008 Sep;28(18):5698-709
pubmed: 18625720
J Cell Biol. 1988 May;106(5):1583-91
pubmed: 3131347
Cancers (Basel). 2020 Mar 19;12(3):
pubmed: 32204315
Mol Med Rep. 2016 Apr;13(4):3533-8
pubmed: 26935238
Curr Opin Cell Biol. 2013 Dec;25(6):780-5
pubmed: 23890995
Cell Div. 2018 Sep 19;13:7
pubmed: 30250494
Bio Protoc. 2018 Sep 5;8(17):
pubmed: 30263905
Cancer Immunol Immunother. 2020 Mar;69(3):449-463
pubmed: 31932876
Ann Oncol. 2013 Nov;24 Suppl 8:viii13-viii21
pubmed: 24131964
BMC Cancer. 2018 May 5;18(1):533
pubmed: 29728077
J Clin Invest. 2012 Apr;122(4):1138-43
pubmed: 22466654
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
NPJ Breast Cancer. 2016;2:
pubmed: 28691057
Nature. 2000 Aug 17;406(6797):747-52
pubmed: 10963602
Mediators Inflamm. 2015;2015:146282
pubmed: 26491220
Cancer Res. 2009 Jan 15;69(2):663-71
pubmed: 19147582
Sci Rep. 2017 Jun 12;7(1):3301
pubmed: 28607365
Oncogene. 2013 Jun 13;32(24):3001-8
pubmed: 22797065
Cancer Res. 2002 Nov 15;62(22):6750-5
pubmed: 12438276
Trends Cell Biol. 2019 Sep;29(9):740-751
pubmed: 31362850
J Clin Oncol. 2009 Mar 10;27(8):1160-7
pubmed: 19204204
Clin Epidemiol. 2019 Jul 11;11:543-561
pubmed: 31372057
Science. 2008 Jun 20;320(5883):1655-8
pubmed: 18566290
Oncogene. 2014 Jul 17;33(29):3764-75
pubmed: 23995787
Oncotarget. 2015 Jun 30;6(18):15772-87
pubmed: 26158218
Cancer Commun (Lond). 2020 Oct;40(10):501-517
pubmed: 32820611
Br J Cancer. 2009 Nov 3;101(9):1606-12
pubmed: 19773755
Clin Cancer Res. 2007 May 15;13(10):2849-54
pubmed: 17504982
Sci Rep. 2017 Mar 22;7:45235
pubmed: 28327601
Trends Cancer. 2018 Oct;4(10):701-712
pubmed: 30292353
Nucleic Acids Res. 2013 Jan;41(Database issue):D955-61
pubmed: 23180760
Clin Cancer Res. 2014 Oct 1;20(19):5085-96
pubmed: 25117293
Exp Cell Res. 2021 Jan 15;398(2):112414
pubmed: 33301764
Tumour Biol. 2017 Mar;39(3):1010428317695968
pubmed: 28351304
J Pathol. 2014 Jan;232(2):142-50
pubmed: 24114677
Nature. 2012 Apr 04;486(7403):395-9
pubmed: 22495314
Cancer Epidemiol Biomarkers Prev. 2014 May;23(5):725-34
pubmed: 24521998
Cell Death Differ. 2008 Jul;15(7):1153-62
pubmed: 18404154
J Androl. 2010 Jan-Feb;31(1):86-94
pubmed: 19875487
Cell Death Differ. 2019 Jan;26(2):199-212
pubmed: 30538286
Cancer Cell. 2020 Apr 13;37(4):514-529
pubmed: 32289274
Nucleic Acids Res. 2019 Jan 8;47(D1):D419-D426
pubmed: 30407594
Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129760
pubmed: 33035602
Cell Res. 1999 Dec;9(4):315-25
pubmed: 10628840
Nat Rev Mol Cell Biol. 2011 Jun;12(6):385-92
pubmed: 21527953
Lancet Oncol. 2015 Apr;16(4):395-405
pubmed: 25728526
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
J Enzyme Inhib Med Chem. 2011 Aug;26(4):579-86
pubmed: 21438710
Nat Rev Cancer. 2004 Apr;4(4):253-65
pubmed: 15057285
Cancer Res. 2019 Dec 1;79(23):5971-5985
pubmed: 31594837
Mol Oncol. 2015 Jan;9(1):140-54
pubmed: 25169932
Biochem Res Int. 2012;2012:951574
pubmed: 22924132
Biochim Biophys Acta. 2008 Sep;1786(1):32-40
pubmed: 18549824