Statins stimulate in vitro membrane FasL expression and lymphocyte apoptosis through RhoA/ROCK pathway in murine melanoma cells.
Neoplasia
; 9(12): 1078-90, 2007 Dec.
Article
en En
| MEDLINE
| ID: mdl-18084615
ABSTRACT
The capacity of FasL molecules expressed on melanoma cells to induce lymphocyte apoptosis contributes to either antitumor immune response or escape depending on their expression level. Little is known, however, about the mechanisms regulating FasL protein expression. Using the murine B16F10 melanoma model weakly positive for FasL, we demonstrated that in vitro treatment with statins, inhibitors of 3-hydroxy-3-methylgutaryl CoA reductase, enhances membrane FasL expression. C3 exotoxin and the geranylgeranyl transferase I inhibitor GGTI-298, but not the farnesyl transferase inhibitor FTI-277, mimic this effect. The capacity of GGTI-298 and C3 exotoxin to inhibit RhoA activity prompted us to investigate the implication of RhoA in FasL expression. Inhibition of RhoA expression by small interfering RNA (siRNA) increased membrane FasL expression, whereas overexpression of constitutively active RhoA following transfection of RhoAV14 plasmid decreased it. Moreover, the inhibition of a RhoA downstream effector p160ROCK also induced this FasL overexpression. We conclude that the RhoA/ROCK pathway negatively regulates membrane FasL expression in these melanoma cells. Furthermore, we have shown that B16F10 cells, through the RhoA/ROCK pathway, promote in vitro apoptosis of Fas-sensitive A20 lymphoma cells. Our results suggest that RhoA/ROCK inhibition could be an interesting target to control FasL expression and lymphocyte apoptosis induced by melanoma cells.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Pirroles
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Melanoma Experimental
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Linfocitos
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Regulación Neoplásica de la Expresión Génica
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Apoptosis
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Inhibidores de Hidroximetilglutaril-CoA Reductasas
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Proteínas de Unión al GTP rho
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Proteína Ligando Fas
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Quinasas Asociadas a rho
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Ácidos Heptanoicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Neoplasia
Asunto de la revista:
NEOPLASIAS
Año:
2007
Tipo del documento:
Article