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

Autor(es)

Ribeiro, Diego Luis ; Latancia, Marcela Teatin ; de Souza, Izadora ; Ariwoola, Abu-Bakr Adetayo ; Mendes, Davi ; Rocha, Clarissa Ribeiro Reily ; Lengert, Andre Van Helvoort ; Menck, Carlos Frederico Martins

• Tipo de documento: Artigo Científico
• Fonte: BIOSCIENCE REPORTS; v. 44, n. 5, p. 18-pg., 2024-05-29.

Resumo

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 (Pol'() 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 Pol'( 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 Pol'( 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 (<= 25 mu M) and promotes cell cycle arrest (G2/M phase) in Pol'( KO spheroids when compared with WTE counterparts. Furthermore, Pol'( 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 Pol'( KO than in WTE spheroids. Collectively, the results suggest that TLS Pol'( 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 Pol'( emerges as a potential therapeutic target for GBM patients. (AU)

• Processo FAPESP: 22/03130-1 - O papel das vias da autofagia e NRF2 na ferroptose
• Beneficiário: Clarissa Ribeiro Reily Rocha
• Modalidade de apoio: Auxílio à Pesquisa - Projeto Inicial
• Processo FAPESP: 21/11597-4 - Análise do papel do gene NRF2 na modulação da ferroptose em linhagens tumorais resistentes a quimioterapia
• Beneficiário: Izadora de Souza
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 20/02836-2 - Mecanismos de resistência de Glioblastoma ao antitumoral temozolomida em células cultivadas como esferoides multicelulares tumorais em três dimensões (3D) in vitro: o papel das polimerases de síntese translesão
• Beneficiário: Diego Luis Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/19435-3 - Papel de danos no DNA e função mitocondrial em envelhecimento vascular, imune e neurológico (DNA MoVINg)
• Beneficiário: Carlos Frederico Martins Menck
• Modalidade de apoio: Auxílio à Pesquisa - Temático