TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors

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art_OLIVEIRA_TOP1_modulation_during_melanoma_progression_and_in_adaptative_2021.PDF.pdf (8.79 MB)
Citações na Scopus
5
Tipo de produção
article
Data de publicação
2021
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Autores
OLIVEIRA, Erica Aparecida de
CHAUHAN, Jagat
SILVA, Julia Rezende da
CARVALHO, Larissa Anastacio da Costa
DIAS, Diogo
CARVALHO, Danielle Goncalves de
WATANABE, Luis Roberto Masao
REBECCA, Vito W.
MILLS, Gordon
LU, Yiling
Citação
PHARMACOLOGICAL RESEARCH, v.173, article ID 105911, 11p, 2021
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
In melanomas, therapy resistance can arise due to a combination of genetic, epigenetic and phenotypic mechanisms. Due to its crucial role in DNA supercoil relaxation, TOP1 is often considered an essential chemotherapeutic target in cancer. However, how TOP1 expression and activity might differ in therapy sensitive versus resistant cell types is unknown. Here we show that TOP1 expression is increased in metastatic melanoma and correlates with an invasive gene expression signature. More specifically, TOP1 expression is highest in cells with the lowest expression of MITF, a key regulator of melanoma biology. Notably, TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi- and BRAFi/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant cells with low TOP1 levels; ii) metastatic cells with high TOP1 levels and high invasiveness; and iii) BRAFi- and BRAFi/MEKi-resistant cells with low TOP1 levels and high invasiveness. Together, these results highlight the potential role of TOP1 in melanoma progression and resistance.
Palavras-chave
Melanoma, TOP1, Resistance, Topotecan, MITF
URI
https://observatorio.fm.usp.br/handle/OPI/44002
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MPT
Artigos e Materiais de Revistas Científicas - HU
Artigos e Materiais de Revistas Científicas - LIM/14
Artigos e Materiais de Revistas Científicas - ODS/03