RESUMEN
Triple negative breast cancer (TNBC) is aggressive with a worse prognosis. We have recently shown that bitter melon extract (BME) treatment was more effective in inhibition of TNBC tumor growth in mouse models as compared to ER positive breast tumor growth. Aberrant dysregulation of lipid metabolism is associated with breast cancer progression, however, anti-cancer mechanism of BME linking lipid metabolism in breast cancer growth remains unexplored. Here, we observed that accumulation of esterified cholesterol was reduced in BME treated TNBC cell lines as compared to control cells. We next evaluated expression levels of acyl-CoA: cholesterol acyltransferase 1 (ACAT-1) in TNBC cells treated with BME. Our results demonstrated that BME treatment inhibited ACAT-1 expression in TNBC cells. Subsequently, we found that sterol regulatory element-binding proteins-1 and -2, and FASN was significantly reduced in BME treated TNBC cell lines. Low-density lipoprotein receptor was also downregulated in BME treated TNBC cells as compared to control cells. We further demonstrated that BME feeding reduced tumor growth in TNBC mammospheres implanted into NSG mice, and inhibits ACAT-1 expression. To our knowledge, this is the first report demonstrating BME suppresses TNBC cell growth through ACAT-1 inhibition, and have potential for additional therapeutic regimen against human breast cancer.
Asunto(s)
Colesterol/metabolismo , Momordica charantia/química , Extractos Vegetales/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo , Acetil-CoA C-Acetiltransferasa/genética , Acetil-CoA C-Acetiltransferasa/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Esterificación/efectos de los fármacos , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Extractos Vegetales/química , Receptores de LDL/genética , Receptores de LDL/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Proteínas de Unión a los Elementos Reguladores de Esteroles/genética , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Lithospermum erythrorhizon, a naphthoquinone compound derived from a shikonin, has long been used as traditional Chinese medicine for treatment of various diseases, including cancer. To evaluate the cytotoxic effects of shikonin on AGS gastric cancer cells via induction of cell cycle arrest. MATERIALS AND METHODS: We observed the effects of 12.5-100 ng/mL dosage of shikonin treatment on AGS cancer cell line with the incubation time of 6h. Cytotoxic effects were assessed by measuring the changes in the intracellular ROS, appearance of senescence phenotype, cell cycle progression, CDK and cyclins expression levels upon shikonin treatment. We also examined upon the activation of Egr1-mediated p21 expression, by siRNA transfection, Luciferase assay, and ChIP assay. RESULTS: In this study, we found that shikonin inhibits cell proliferation by arresting cell cycle progression at the G2/M phase via modulation of p21 in AGS cells. Also, our results revealed that the p21 gene was transactivated by early growth response1 (Egr1) in response to the shikonin treatment. Transient Egr1 expression enhanced shikonin-induced p21 promoter activity, whereas the suppression of Egr1 expression by small interfering RNA attenuated the ability of shikonin to induce p21 promoter activity. CONCLUSION: Our results suggested that the anti-proliferative activity of shikonin was due to its ability to induce cell cycle arrest via Egr1-p21 signaling pathway. Thus, the work stated here validates the traditional use of shikonin in the treatment of cancer.