Temozolomide resistance mechanisms: unveiling the role of translesion DNA polymerase kappa in glioblastoma spheroids in vitro.

Autor:	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.
Jazyk:	angličtina
Zdroj:	Bioscience reports [Biosci Rep] 2024 May 29; Vol. 44 (5).
DOI:	10.1042/BSR20230667
Abstrakt:	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).)
Databáze:	MEDLINE
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