Oxysterols synergize with statins by inhibiting SREBP-2 in ovarian cancer cells.
Gynecol Oncol
; 135(2): 333-41, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25134999
ABSTRACT
OBJECTIVE:
Determine mechanisms responsible for enhanced statin efficacy in a novel statin combination we name STOX (STatin-OXysterol).METHODS:
Ovarian cancer cell lines were treated with combinations of statins and oxysterols. Cell viability was determined by a modified MTT assay. Apoptosis was evaluated by immunoblotting of PARP and DAPI-mediated visualization of apoptotic nuclei. STOX effects on the expression of genes of the mevalonate pathway were assessed by real-time qPCR and immunoblotting. siRNA-mediated gene silencing was used to test the involvement of oxysterol-mediated repression of SREBP-2 in STOX synergy. The impact of statin-mediated inhibition of protein prenylation and on cholesterol homeostasis was evaluated.RESULTS:
Oxysterols dramatically enhance cytotoxicity of statins in ovarian cancer cells through increased apoptosis. Decreased expression of SREBP-2 down-regulates the mevalonate pathway and prevents the active statin-induced sterol feedback, enhancing statin toxicity. Comparison of two ovarian cancer cell lines reveals two distinct mechanisms of statin induced toxicity, namely, dependence on protein geranylgeranylation and/or perturbation of cellular cholesterol levels.CONCLUSIONS:
We provide evidence of statins' mechanisms of cytotoxicity in different ovarian cancer cells and discovered a new approach to significantly enhance the anti-tumor activity of statins. These observations provide a potential new path to improve statins as a treatment against ovarian cancer with obtainable dosages.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Apoptose
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Neoplasias Epiteliais e Glandulares
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Inibidores de Hidroximetilglutaril-CoA Redutases
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Sinvastatina
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Proteína de Ligação a Elemento Regulador de Esterol 2
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Hidroxicolesteróis
Limite:
Female
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Humans
Idioma:
En
Revista:
Gynecol Oncol
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos