دورية أكاديمية
Temozolomide resistance mechanisms: unveiling the role of translesion DNA polymerase kappa in glioblastoma spheroids in vitro.
العنوان: | Temozolomide resistance mechanisms: unveiling the role of translesion DNA polymerase kappa in glioblastoma spheroids in vitro. |
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المؤلفون: | Ribeiro DL; Departament of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil., Latancia MT; Departament of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil., de Souza I; Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo, São Paulo, Brazil., Ariwoola AA; Departament of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.; Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo, São Paulo, Brazil., Mendes D; Departament of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil., Rocha CRR; Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo, São Paulo, Brazil., Lengert AVH; Department of Biophysics, Paulista School of Medicine, Federal University of São Paulo, São Paulo, São Paulo, Brazil., Menck CFM; Departament of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil. |
المصدر: | Bioscience reports [Biosci Rep] 2024 May 29; Vol. 44 (5). |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 8102797 Publication Model: Print Cited Medium: Internet ISSN: 1573-4935 (Electronic) Linking ISSN: 01448463 NLM ISO Abbreviation: Biosci Rep Subsets: MEDLINE |
أسماء مطبوعة: | Publication: London : Portland Press on behalf of the Biochemical Society Original Publication: London : The Biochemical Society, c1981- |
مواضيع طبية MeSH: | Glioblastoma*/drug therapy , Glioblastoma*/pathology , Glioblastoma*/genetics , Glioblastoma*/enzymology , Temozolomide*/pharmacology , Drug Resistance, Neoplasm*/drug effects , DNA-Directed DNA Polymerase*/metabolism , DNA-Directed DNA Polymerase*/genetics , Spheroids, Cellular*/drug effects , Spheroids, Cellular*/pathology, Humans ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; Apoptosis/drug effects ; Brain Neoplasms/drug therapy ; Brain Neoplasms/pathology ; Brain Neoplasms/genetics ; Brain Neoplasms/enzymology ; Antineoplastic Agents, Alkylating/pharmacology |
مستخلص: | Temozolomide (TMZ) is the leading therapeutic agent for combating Glioblastoma Multiforme (GBM). Nonetheless, the persistence of chemotherapy-resistant GBM cells remains an ongoing challenge, attributed to various factors, including the translesion synthesis (TLS) mechanism. TLS enables tumor cells to endure genomic damage by utilizing specialized DNA polymerases to bypass DNA lesions. Specifically, TLS polymerase Kappa (Polκ) has been implicated in facilitating DNA damage tolerance against TMZ-induced damage, contributing to a worse prognosis in GBM patients. To better understand the roles of Polκ in TMZ resistance, we conducted a comprehensive assessment of the cytotoxic, antiproliferative, antimetastatic, and genotoxic effects of TMZ on GBM (U251MG) wild-type (WTE) and TLS Polκ knockout (KO) cells, cultivated as three-dimensional (3D) tumor spheroids in vitro. Initial results revealed that TMZ: (i) induces reductions in GBM spheroid diameter (10-200 µM); (ii) demonstrates significant cytotoxicity (25-200 μM); (iii) exerts antiproliferative effects (≤25 μM) and promotes cell cycle arrest (G2/M phase) in Polκ KO spheroids when compared with WTE counterparts. Furthermore, Polκ KO spheroids exhibit elevated levels of cell death (Caspase 3/7) and display greater genotoxicity (53BP1) than WTE following TMZ exposure. Concerning antimetastatic effects, TMZ impedes invadopodia (3D invasion) more effectively in Polκ KO than in WTE spheroids. Collectively, the results suggest that TLS Polκ plays a vital role in the survival, cell death, genotoxicity, and metastatic potential of GBM spheroids in vitro when subjected to TMZ treatment. While the precise mechanisms underpinning this resistance remain elusive, TLS Polκ emerges as a potential therapeutic target for GBM patients. (© 2024 The Author(s).) |
References: | Mutat Res Rev Mutat Res. 2016 Jul-Sep;769:19-35. (PMID: 27543314) J Neurooncol. 2012 Apr;107(2):359-64. (PMID: 22045118) Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772) Oncotarget. 2015 Aug 28;6(25):21255-67. (PMID: 26101913) J Cell Sci. 2012 Apr 1;125(Pt 7):1633-43. (PMID: 22499669) J Cell Sci. 2017 Jan 15;130(2):512-520. (PMID: 27888217) Neuro Oncol. 2010 Jul;12(7):679-86. (PMID: 20164241) Cancer Epidemiol Biomarkers Prev. 2014 Oct;23(10):1985-96. (PMID: 25053711) Acta Naturae. 2022 Jan-Mar;14(1):92-100. (PMID: 35441052) Cancer Res. 2016 Apr 15;76(8):2340-53. (PMID: 26960975) Chem Res Toxicol. 2016 Jan 19;29(1):101-8. (PMID: 26651356) PLoS One. 2013 Apr 23;8(4):e62630. (PMID: 23626842) Cancer Sci. 2017 Apr;108(4):704-712. (PMID: 28135769) Sci Rep. 2015 May 18;5:10129. (PMID: 25984718) Mol Cell. 2017 Jun 15;66(6):801-817. (PMID: 28622525) Chem Biol Drug Des. 2021 Jul;98(1):144-165. (PMID: 33963665) Cancer Drug Resist. 2021;4:17-43. (PMID: 34337348) Mol Neurobiol. 2018 Mar;55(3):2506-2515. (PMID: 28391554) Adv Drug Deliv Rev. 2014 Dec 15;79-80:155-71. (PMID: 25109853) Methods Mol Biol. 2011;740:103-14. (PMID: 21468972) Cancer Res. 2019 Jan 1;79(1):99-113. (PMID: 30361254) Chem Res Toxicol. 2017 Nov 20;30(11):1942-1955. (PMID: 28841374) Biofabrication. 2021 Apr 08;13(3):. (PMID: 33592595) J Vis Exp. 2020 Apr 9;(158):. (PMID: 32338647) Cells. 2020 Dec 01;9(12):. (PMID: 33271924) Life Sci. 2021 Dec 15;287:120128. (PMID: 34774874) Nat Rev Cancer. 2023 Jan;23(1):6-24. (PMID: 36323800) Arch Oral Biol. 2012 Apr;57(4):335-43. (PMID: 21920495) Biochemistry. 2016 Sep 20;55(37):5218-29. (PMID: 27525498) J Vis Exp. 2015 Nov 20;(105):. (PMID: 26649463) DNA Repair (Amst). 2022 Apr;112:103303. (PMID: 35219626) Cancer Res. 2009 Jan 1;69(1):120-7. (PMID: 19117994) Mol Cell Biol. 2009 Jun;29(11):3113-23. (PMID: 19332561) Nat Protoc. 2009;4(3):309-24. (PMID: 19214182) Int J Mol Sci. 2021 Apr 10;22(8):. (PMID: 33920223) DNA Repair (Amst). 2019 Jun;78:20-26. (PMID: 30954011) Wiley Interdiscip Rev Dev Biol. 2015 Sep-Oct;4(5):469-87. (PMID: 25827130) BMC Biol. 2012 Mar 22;10:29. (PMID: 22439642) PLoS Genet. 2017 Aug 17;13(8):e1006842. (PMID: 28817566) Cell Biol Toxicol. 2020 Apr;36(2):145-164. (PMID: 31820165) Nat Protoc. 2006;1(5):2315-9. (PMID: 17406473) Nat Rev Cancer. 2011 Feb;11(2):96-110. (PMID: 21258395) J Vis Exp. 2015 May 01;(99):e52686. (PMID: 25993495) Int J Radiat Biol. 2007 Nov-Dec;83(11-12):849-71. (PMID: 18058370) Sci Rep. 2018 May 8;8(1):7222. (PMID: 29740146) Clin Exp Med. 2013 Nov;13(4):279-88. (PMID: 22828727) Biomedicines. 2019 Sep 09;7(3):. (PMID: 31505812) BMC Cancer. 2012 Jan 13;12:15. (PMID: 22244109) Nat Rev Cancer. 2012 Jan 12;12(2):104-20. (PMID: 22237395) Cancers (Basel). 2021 Sep 11;13(18):. (PMID: 34572787) ACS Chem Biol. 2019 Jun 21;14(6):1337-1351. (PMID: 31082191) Mutat Res Genet Toxicol Environ Mutagen. 2018 Dec;836(Pt B):127-142. (PMID: 30442338) Mutat Res Genet Toxicol Environ Mutagen. 2022 Jun;878:503498. (PMID: 35649682) Drug Resist Updat. 2021 Mar;55:100753. (PMID: 33667959) Methods Mol Biol. 2013;986:253-66. (PMID: 23436417) Clin Cancer Res. 2007 May 15;13(10):3033-42. (PMID: 17505006) Nucleic Acids Res. 2016 Jul 8;44(12):5717-31. (PMID: 27095204) Sci Adv. 2020 Jun 10;6(24):eaaz7808. (PMID: 32577513) PLoS One. 2015 Jun 19;10(6):e0130348. (PMID: 26090664) Cancer. 2016 Jul 15;122(14):2206-15. (PMID: 27088883) Cancer Res. 2018 Feb 15;78(4):1083-1096. (PMID: 29259011) Cancer Discov. 2022 Jan;12(1):31-46. (PMID: 35022204) Expert Opin Drug Discov. 2019 Mar;14(3):289-301. (PMID: 30689452) Cancer Drug Resist. 2020 Aug 07;3(3):287-301. (PMID: 35582442) BMC Cancer. 2013 Feb 27;13:95. (PMID: 23446043) Mutat Res. 2009 Aug;678(2):76-94. (PMID: 19465146) Mol Cell Biol. 2021 Oct 26;41(11):e0009021. (PMID: 34398682) Cancers (Basel). 2022 May 13;14(10):. (PMID: 35626018) Front Endocrinol (Lausanne). 2018 Jun 15;9:318. (PMID: 29963012) Nat Cell Biol. 2006 Jun;8(6):640-2. (PMID: 16738703) |
معلومات مُعتمدة: | #308868/2018-8 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); financial code 001 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); #2020/02836-2 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); #2019/19435-3 and #2013/08028-1 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); #2021/11597-4 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); #2022/03130-1 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) |
فهرسة مساهمة: | Keywords: 3D spheroids; Genotoxicity; Glioma; Temozolomide; Translesion Synthesis; apoptosis |
المشرفين على المادة: | YF1K15M17Y (Temozolomide) EC 2.7.7.7 (DNA-Directed DNA Polymerase) EC 2.7.7.7 (POLK protein, human) 0 (Antineoplastic Agents, Alkylating) |
تواريخ الأحداث: | Date Created: 20240508 Date Completed: 20240529 Latest Revision: 20240603 |
رمز التحديث: | 20240603 |
مُعرف محوري في PubMed: | PMC11139666 |
DOI: | 10.1042/BSR20230667 |
PMID: | 38717250 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1573-4935 |
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DOI: | 10.1042/BSR20230667 |