RESUMO
The primary aim of this study was to find novel chemopreventive agents effective against breast cancer. Endoplasmic reticulum (ER) stress can induce apoptosis through the unfolded protein response (UPR). 2'-Hydroxy-2,3,5'-trimethoxychalcone (DK143) is a synthetic flavonoid derivative. The present study provides evidence supporting the role of the UPR in mediating the apoptotic effect of DK143. Treatment with DK143 triggered apoptosis through the activation of the caspase pathway in MDA-MB-231 breast cancer cells without affecting viability of MCF10A non-transformed breast epithelial cells. Further analysis revealed that DK143 produced reactive oxygen species (ROS) in MDA-MB-231 cells, but not in MCF10A cells, and upregulated the expression of ER stress sensors, including GRP78/BiP, IRE1α, CHOP, and Bim in MDA-MB-231 cells. In addition, UPR-related transcription factors, XBP-1 and CHOP, were activated by DK143. Moreover, silencing of IRE1α or CHOP by corresponding siRNA molecules attenuated DK143-induced apoptosis. Furthermore, DK143 suppressed mouse tumor growth in vivo. These results demonstrate that promoting ER stress in breast cancer cells via UPR induction might be a promising strategy for developing new chemotherapeutic or chemopreventive agents for breast cancer.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalconas/síntese química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Chaperona BiP do Retículo Endoplasmático , Endorribonucleases/genética , Endorribonucleases/metabolismo , Feminino , Proteínas de Choque Térmico/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Transfecção , Carga Tumoral/efeitos dos fármacosRESUMO
2-Hydroxy-3',5,5'-trimenthoxyochalcone (DK-139) is a synthetic chalcone-derived compound. This study evaluated the biological activity of DK-139 on the inhibition of tumor metastasis. Growth-regulated oncogene-alpha (GROα) plays an important role in the progression of tumor development by stimulating angiogenesis and metastasis. In this study, DK-139 inhibited tumor necrosis factor alpha (TNFα)-induced GROα gene promoter activity by inhibiting of IκB kinase (IKK) in MDA-MB231 cells. In addition, DK-139 prevented the TNFα-induced cell migration, F-actin formation, and invasive capability of MDA-MB-231 cells. These findings suggest that DK-139 is a potential drug candidate for the inhibition of tumor cell locomotion and invasion via the suppression of NF-κB-mediated GROα expression.