Energystressmediated activation of AMPK sensitizes MPS1 kinase inhibition in triplenegative breast cancer.
Oncol Rep
; 52(2)2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38904203
ABSTRACT
Monopolar spindle 1 kinase (Mps1, also known as TTK protein kinase) inhibitors exert marked anticancer effects against triplenegative breast cancer (TNBC) by causing genomic instability and cell death. As aneuploid cells are vulnerable to compounds that induce energy stress through adenosine monophosphateactivated protein kinase (AMPK) activation, the synergistic effect of Mps1/TTK inhibition and AMPK activation was investigated in the present study. The combined effects of CFI402257, an Mps1/TTK inhibitor, and AICAR, an AMPK agonist, were evaluated in terms of cytotoxicity, cellcycle distribution, and in vivo xenograft models. Additional molecular mechanistic studies were conducted to elucidate the mechanisms underlying apoptosis and autophagic cell death. The combination of CFI402257 and AICAR showed selective cytotoxicity in a TNBC cell line. The formation of polyploid cells was attenuated, and apoptosis was increased by the combination treatment, which also induced autophagy through dual inhibition of the PI3K/Akt/mTOR and mitogenactivated protein kinase (MAPK) signaling pathways. Additionally, the combination therapy showed strongly improved efficacy in comparison with CFI402257 and AICAR monotherapy in the MDAMB231 xenograft model. The present study suggested that the combination of CFI402257 and AICAR is a promising therapeutic strategy for TNBC.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Ribonucleotídeos
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Autofagia
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Proteínas Serina-Treonina Quinases
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Apoptose
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Proteínas de Ciclo Celular
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Ensaios Antitumorais Modelo de Xenoenxerto
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Proteínas Quinases Ativadas por AMP
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Neoplasias de Mama Triplo Negativas
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Aminoimidazol Carboxamida
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article