Busca avançada
Ano de início
Entree
(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Targeting the Oncogenic TBX2 Transcription Factor With Chromomycins

Texto completo
Autor(es):
Mostrar menos -
Sahm, Bianca Del B. [1] ; Peres, Jade [2] ; Rezende-Teixeira, Paula [1] ; Santos, Evelyne A. [3] ; Branco, Paola C. [1] ; Bauermeister, Anelize [4, 1] ; Kimani, Serah [2] ; Moreira, Eduarda A. [4] ; Bisi-Alves, Renata [3] ; Bellis, Claire [2] ; Mlaza, Mihlali [2] ; Jimenez, Paula C. [5] ; Lopes, Norberto P. [4] ; Machado-Santelli, Glaucia M. [3] ; Prince, Sharon [1, 2] ; Costa-Lotufo, V, Leticia
Número total de Autores: 16
Afiliação do(s) autor(es):
[1] V, Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil
[2] Univ Cape Town, Dept Human Biol, Div Cell Biol, Cape Town - South Africa
[3] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, Sao Paulo - Brazil
[4] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Phys & Chem, Ribeirao Preto - Brazil
[5] Univ Fed Sao Paulo, Dept Sea Sci, Santos - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN CHEMISTRY; v. 8, MAR 3 2020.
Citações Web of Science: 0
Resumo

The TBX2 transcription factor plays critical roles during embryonic development and it is overexpressed in several cancers, where it contributes to key oncogenic processes including the promotion of proliferation and bypass of senescence. Importantly, based on compelling biological evidences, TBX2 has been considered as a potential target for new anticancer therapies. There has therefore been a substantial interest to identify molecules with TBX2-modulatory activity, but no such substance has been found to date. Here, we adopt a targeted approach based on a reverse-affinity procedure to identify the ability of chromomycins A(5) (CA(5)) and A(6) (CA(6)) to interact with TBX2. Briefly, a TBX2-DNA-binding domain recombinant protein was N-terminally linked to a resin, which in turn, was incubated with either CA(5) or CA(6). After elution, bound material was analyzed by UPLC-MS and CA(5) was recovered from TBX2-loaded resins. To confirm and quantify the affinity (K-D) between the compounds and TBX2, microscale thermophoresis analysis was performed. CA(5) and CA(6) modified the thermophoretic behavior of TBX2, with a K-D in micromolar range. To begin to understand whether these compounds exerted their anti-cancer activity through binding TBX2, we next analyzed their cytotoxicity in TBX2 expressing breast carcinoma, melanoma and rhabdomyosarcoma cells. The results show that CA(5) was consistently more potent than CA(6) in all tested cell lines with IC50 values in the nM range. Of the cancer cell types tested, the melanoma cells were most sensitive. The knockdown of TBX2 in 501mel melanoma cells increased their sensitivity to CA(5) by up to 5 times. Furthermore, inducible expression of TBX2 in 501mel cells genetically engineered to express TBX2 in the presence of doxycycline, were less sensitive to CA(5) than the control cells. Together, the data presented in this study suggest that, in addition to its already recognized DNA-binding properties, CA(5) may be binding the transcription factor TBX2, and it can contribute to its cytotoxic activity. (AU)

Processo FAPESP: 18/24865-4 - Novas abordagens em metabolômica: cartografia molecular 3D de ascídias baseado em dados de LC-MS/MS
Beneficiário:Anelize Bauermeister
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
Processo FAPESP: 15/17177-6 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer
Beneficiário:Leticia Veras Costa Lotufo
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 19/02008-5 - Substâncias marinhas que induzem Dano ao DNA e inibem o TBX2 como uma nova estratégia para tratar câncer de mama
Beneficiário:Leticia Veras Costa Lotufo
Linha de fomento: Auxílio à Pesquisa - Pesquisador Visitante - Internacional
Processo FAPESP: 18/08400-1 - Substâncias marinhas que induzem dano ao DNA e inibem TBX2 como uma nova estratégia no tratamento do câncer
Beneficiário:Leticia Veras Costa Lotufo
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 17/09022-8 - Proteínas inibidoras da apoptose (IAPs) como alvo terapêutico no melanoma: estudos com prodigininas em células resistentes ao vemurafenibe
Beneficiário:Paola Cristina Branco
Linha de fomento: Bolsas no Brasil - Pós-Doutorado