RESUMO
ß-Thujaplicin, a natural monoterpenoid, has been demonstrated to exert health beneficial activities in chronic diseases. However, it has not been studied in regulating estrogen receptor (ER) negative breast cancer. Here, we investigated the effect of ß-thujaplicin on inhibiting ER-negative basal-like breast cancer and the underlying mechanism of action using an in vitro and in vivo xenograft animal model. ß-Thujaplicin induced G0/G1 phase cell cycle arrest and regulated cell cycle mediators, cyclin D1, cyclin E, and cyclin-dependent kinase 4 (CDK 4), leading to the inhibition of the proliferation of ER-negative basal-like MCF10DCIS.com human breast cancer cells. It also modulated the phosphorylation of protein kinase B (AKT) and glycogen synthase kinase (GSK-3ß) and the protein level of ß-catenin. In an MCF10DCIS.com xenograft animal model, ß-thujaplicin significantly inhibited tumor growth, reduced tumor weight, and regulated the expression of cell cycle proteins, phosphorylation of AKT and GSK-3ß, and protein level of ß-catenin in the tumor tissues. These results demonstrate that ß-thujaplicin can suppress basal-like mammary tumor growth by regulating GSK-3ß/ß-catenin signaling, suggesting that ß-thujaplicin may be a potent chemopreventive agent against the basal-like subtype of breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Glicogênio Sintase Quinase 3 beta/metabolismo , Monoterpenos/administração & dosagem , Tropolona/análogos & derivados , beta Catenina/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chamaecyparis/química , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Thuja/química , Tropolona/administração & dosagem , beta Catenina/genéticaRESUMO
In breast cancer, the cytokine tumor necrosis factor-α (TNF-α) induces cell invasion, although the molecular basis of it has not been clearly elucidated. In this study, we investigated the role of daidzein in regulating TNF-α induced cell invasion and the underlying molecular mechanisms. Daidzein inhibited TNF-α induced cellular migration and invasion in estrogen receptor (ER) negative MCF10DCIS.com human breast cancer cells. TNF-α activated Hedgehog (Hh) signaling by enhancing Gli1 nuclear translocation and transcriptional activity, which resulted in increased invasiveness; these effects were blocked by daidzein and the Hh signaling inhibitors, cyclopamine and vismodegib. Moreover, these compounds suppressed TNF-α induced matrix metalloproteinase (MMP)-9 mRNA expression and activity. Taken together, mammary tumor cell invasiveness was stimulated by TNF-α induced activation of Hh signaling; these effects were abrogated by daidzein, which suppressed Gli1 activation, thereby inhibiting migration and invasion.