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Control de la reprogramación metabólica inducida por el estrés nutricional por PKCζ en la tumorigénesis
Li Ma1, Yongzhen Tao, Angeles Duran
1Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Cell
|February 5, 2013
Resumen
La deficiencia de la proteína quinasa C zeta (PKCζ) permite a las células cancerosas adaptarse al metabolismo, utilizando la glutamina a través de la vía biosintética de la serina. La pérdida de PKCζ mejora el crecimiento tumoral, lo que indica su papel como supresor metabólico del tumor.
Área de la Ciencia:
- Oncología Oncología.
- El metabolismo del cáncer.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Las células tumorales exhiben altas demandas metabólicas y se adaptan al estrés nutricional para la supervivencia y la proliferación.
- La reprogramación metabólica es un sello distintivo del cáncer, lo que permite un crecimiento sostenido en condiciones difíciles.
Objetivo del estudio:
- Investigar el papel de la proteína quinasa C zeta (PKCζ) en la regulación del metabolismo de las células cancerosas y su impacto en la tumorigénesis.
- Para dilucidar los mecanismos moleculares por los cuales PKCζ influye en las vías metabólicas cruciales para la supervivencia de las células cancerosas.
Principales métodos:
- Estudió el efecto de la deficiencia de PKCζ en el metabolismo de las células cancerosas, centrándose en la utilización de la glutamina y la vía biosintética de la serina.
- Analizó la expresión y actividad de las enzimas clave PHGDH y PSAT1 en respuesta a los niveles de PKCζ.
- Se utilizaron modelos de ratón de tumorigénesis intestinal y se analizaron muestras de tumores intestinales humanos.
Principales resultados:
- La deficiencia de PKCζ promueve la plasticidad metabólica, permitiendo a las células cancerosas utilizar la glutamina a través de la vía biosintética de la serina cuando la glucosa está limitada.
- PKCζ reprime la expresión de PHGDH y PSAT1 e inhibe la actividad de PHGDH a través de la fosforilación.
- La pérdida de PKCζ en ratones conduce a un aumento de la tumorigénesis intestinal y niveles elevados de PHGDH y PSAT1.
- Los bajos niveles de PKCζ en pacientes con cáncer humano se correlacionan con un mal pronóstico y están asociados con los niveles de PHGDH.
Conclusiones:
- La PKCζ actúa como un supresor tumoral metabólico crítico tanto en cánceres de ratón como en humanos.
- La PKCζ regula el metabolismo de las células cancerosas mediante el control de la vía biosintética de la serina, lo que afecta el crecimiento del tumor y los resultados del paciente.
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