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La inhibición de la piruvatocinasa M2 por especies reactivas de oxígeno contribuye a las respuestas antioxidantes
Dimitrios Anastasiou1, George Poulogiannis, John M Asara
1Beth Israel Deaconess Medical Center, Department of Medicine-Division of Signal Transduction, Boston, MA 02115, USA.
Science (New York, N.Y.)
|November 5, 2011
Resumen
Las células cancerosas controlan las especies reactivas de oxígeno (ROS) utilizando piruvato quinasa M2 (PKM2). La PKM2 oxidada desvía la glucosa a la vía de la pentosa fosfato, ayudando a la desintoxicación de las ROS y la formación de tumores.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología del cáncer Biología del cáncer.
- Metabolismo celular El metabolismo celular es el metabolismo celular.
Sus antecedentes:
- Las concentraciones de especies reactivas de oxígeno (ROS) intracelulares son críticas para la supervivencia de las células cancerosas.
- La piruvato quinasa M2 (PKM2) juega un papel clave en el metabolismo y la proliferación de las células cancerosas.
Objetivo del estudio:
- Para investigar el papel de PKM2 en la regulación de las concentraciones intracelulares de ROS en las células de cáncer de pulmón humano.
- Determinar el mecanismo por el cual las ROS afectan la actividad de PKM2.
- Evaluar el impacto de la modulación de la resistencia a la oxidación de PKM2 en la supervivencia de las células cancerosas y la formación de tumores.
Principales métodos:
- Utilizó líneas celulares de cáncer de pulmón humano.
- Investigó el efecto de los aumentos agudos de las ROS intracelulares en la actividad de PKM2.
- Se analizó la oxidación de Cys(358) en PKM2.
- Mutagénesis dirigida en el sitio empleada para crear un mutante PKM2 resistente a la oxidación (Cys358 a Ser358).
- Se evaluó la sensibilidad de las células cancerosas al estrés oxidativo.
- Evaluación de la formación de tumores en un modelo de ratón xenograft.
Principales resultados:
- Los aumentos agudos en las ROS intracelulares inhiben la PKM2 a través de la oxidación de Cys{358}.
- La inhibición de PKM2 por ROS es esencial para desviar el flujo de glucosa hacia la vía de la pentosa fosfato.
- Este cambio metabólico genera un potencial de reducción para la desintoxicación de los ROS.
- Las células de cáncer de pulmón con PKM2 resistente a la oxidación mostraron una mayor sensibilidad al estrés oxidativo.
- Se observó un deterioro en la formación de tumores en modelos de xenotransplante utilizando células con PKM2.2, resistentes a la oxidación.
Conclusiones:
- Las propiedades reguladoras de PKM2 permiten a las células cancerosas soportar el estrés oxidativo.
- La modulación de la oxidación de PKM2 ofrece una estrategia terapéutica potencial para atacar las células cancerosas.
- El papel de PKM2 se extiende más allá de la proliferación, contribuyendo a la supervivencia de las células cancerosas bajo estrés oxidativo.
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