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La vía mTORC1 estimula el metabolismo de la glutamina y la proliferación celular al reprimir la SIRT4
Alfred Csibi1, Sarah-Maria Fendt, Chenggang Li
1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell
|May 14, 2013
Resumen
El objetivo mamífero del complejo de rapamicina 1 (mTORC1) activa el metabolismo de la glutamina al inhibir SIRT4, un regulador clave de la deshidrogenasa de glutamato (GDH). Esta vía es crucial en el cáncer, lo que sugiere nuevos objetivos terapéuticos.
Área de la Ciencia:
- El metabolismo celular es el metabolismo celular.
- Biología molecular La biología molecular.
- Investigación de la investigación del cáncer.
Sus antecedentes:
- Las células proliferantes utilizan la glutamina para la biosíntesis y la energía.
- El objetivo mamífero del complejo de rapamicina 1 (mTORC1) está relacionado con el aumento del metabolismo de los nutrientes.
- El vínculo molecular entre mTORC1 y la glutaminólisis no estaba claro.
Objetivo del estudio:
- Para dilucidar el mecanismo molecular por el cual mTORC1 influye en el metabolismo de la glutamina.
- Para investigar el papel de SIRT4 en la glutaminólisis mediada por mTORC1.
- Explorar el potencial terapéutico de dirigirse a esta vía en el cáncer.
Principales métodos:
- Investigó el efecto de la activación de mTORC1 en la actividad de la glutamato deshidrogenasa (GDH).
- Se evaluó el papel de SIRT4 en la regulación de la GDH.
- Se examinó el impacto de mTORC1 en la expresión y estabilidad de SIRT4 a través de CREB2.
- Se analizó la expresión de SIRT4 en tejidos cancerosos humanos.
- Se evaluó el efecto de la sobreexpresión de SIRT4 en la proliferación de células cancerosas y el desarrollo de tumores.
Principales resultados:
- La activación de mTORC1 promueve la anaplerosis por glutamina mediante la activación de la GDH.
- Esta activación está mediada por la represión transcripcional de SIRT4, un inhibidor de la GDH.
- mTORC1 desestabiliza CREB2, lo que lleva a una reducción de la expresión de SIRT4.
- La expresión de SIRT4 está disminuida en los cánceres humanos.
- La sobreexpresión de SIRT4 inhibe la proliferación, la transformación y el crecimiento tumoral de las células cancerosas.
Conclusiones:
- mTORC1 regula el metabolismo de la glutamina a través del eje SIRT4/GDH.
- La vía mTORC1-SIRT4 está implicada en el desarrollo del cáncer.
- Dirigirse al metabolismo de los nutrientes en los cánceres con alto contenido de mTORC1 presenta una estrategia terapéutica potencial.
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