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Los tumores con activación de PI3K son resistentes a las restricciones dietéticas
Nada Y Kalaany1, David M Sabatini
1Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature
|March 13, 2009
Resumen
La restricción dietética afecta el crecimiento tumoral, pero la resistencia está vinculada a la vía de la fosfatidilinositol-3-quinasa (PI3K). La activación de mutaciones en PI3K hace que los tumores sean resistentes a la restricción dietética, lo que sugiere terapias dirigidas.
Área de la Ciencia:
- Oncología Oncología.
- Las vías metabólicas.
- Biología del cáncer Biología del cáncer.
Sus antecedentes:
- Se sabe que la restricción dietética (RD) retrasa la incidencia de tumores y ralentiza el crecimiento tumoral.
- Los mecanismos subyacentes para la sensibilidad tumoral o la resistencia a la DR no se comprenden completamente.
Objetivo del estudio:
- Investigar los mecanismos moleculares que determinan la sensibilidad de las células cancerosas a la restricción dietética.
- Identificar vías específicas que confieren resistencia a los efectos anti-crecimiento de la DR.
Principales métodos:
- Utilizó líneas de células cancerosas humanas cultivadas como xenografts tumorales en ratones.
- Crecimiento tumoral comparado y sensibilidad a la DR en líneas celulares con activación variable de la vía PI3K.
- Células cancerosas modificadas genéticamente para alterar la actividad de la vía PI3K (por ejemplo, sustituyendo el PI3K mutante por el tipo salvaje, restaurando la expresión de PTEN).
- Efectos evaluados de DR en modelos de ratón PTEN-nulo de cáncer de próstata y un modelo de cáncer de pulmón que carece de señalización PI3K constitutiva.
Principales resultados:
- Las líneas de células cancerosas con la vía de la fosfatidilinositol-3-quinasa (PI3K) activada constitutivamente mostraron resistencia a los efectos anti-crecimiento de la DR.
- Estas células resistentes podrían proliferar independientemente de la insulina o el factor de crecimiento similar a la insulina 1.
- La restauración de la expresión de PI3K o PTEN de tipo salvaje convirtió los tumores resistentes a un fenotipo sensible a DR.
- La DR no afectó el crecimiento del cáncer de próstata PTEN-nulo, pero redujo la carga tumoral en un modelo de cáncer de pulmón independiente de PI3K.
Conclusiones:
- La vía PI3K es un determinante crítico de la sensibilidad tumoral a la restricción dietética.
- La activación de mutaciones en la vía PI3K confiere resistencia a DR.
- Estos hallazgos sugieren que el estado de activación de la vía PI3K puede predecir la respuesta del cáncer a las terapias DR-miméticas.
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