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Transformación por el (R) -enantiómero del 2-hidroxiglutarato vinculado a la activación de la EGLN

Peppi Koivunen¹, Sungwoo Lee, Christopher G Duncan

¹Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.

|February 21, 2012

Resumen

Las mutaciones en la isocitrato deshidrogenasa (IDH) producen (R)-2-hidroxiglutarato, que mejora la proliferación celular al inhibir las enzimas EGLN y reducir los niveles de factor inducible a la hipoxia (HIF). Esto sugiere la inhibición de EGLN como un tratamiento potencial para el cáncer.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología del cáncer Biología del cáncer.
Regulación del metabolismo La regulación del metabolismo

Sus antecedentes:

Las mutaciones en la succinato deshidrogenasa (SDH), fumarato hidratasa (FH) y isocitrato deshidrogenasa (IDH) están relacionadas con el desarrollo del cáncer.
Las mutaciones SDH y FH conducen a la acumulación de metabolitos, inhibiendo las enzimas involucradas en la regulación del factor inducible a la hipoxia (HIF).
Las mutaciones de IDH en tumores cerebrales y leucemias resultan en la producción de (R)-2-hidroxiglutarato ((R)-2HG).

Objetivo del estudio:

Investigar el papel de (R)-2HG, un metabolito producido por enzimas mutadas de IDH, en la patogénesis del cáncer.
Para dilucidar el mecanismo por el cual (R) - 2HG influye en los procesos celulares relevantes para el crecimiento tumoral.
Explorar estrategias terapéuticas potenciales dirigidas a las alteraciones metabólicas en los cánceres mutantes en IDH.

Principales métodos:

Análisis de los efectos de los metabolitos en la actividad de la EGLN prolyl hidroxilasa.
Evaluación de los niveles del factor inducible a la hipoxia (HIF) en respuesta a (R) - 2HG.
Evaluación de la proliferación de astrocitos y el crecimiento independiente del anclaje en presencia de (R) - 2HG.

Principales resultados:

Se encontró que (R)-2HG, pero no (S)-2HG, estimula la actividad de EGLN.
La estimulación de EGLN por (R) - 2HG condujo a la disminución de los niveles de HIF.
Los niveles reducidos de HIF mejoraron la proliferación y el crecimiento de agar blando de los astrocitos humanos.

Conclusiones:

El estudio identifica un mecanismo específico del enantiómero donde (R) - 2HG promueve la transformación en cánceres mutantes de IDH.
La acumulación de (R)-2HG en tumores mutantes en IDH contribuye a la patogénesis al alterar los niveles de HIF.
La inhibición de las enzimas EGLN presenta una potencial vía terapéutica para los cánceres mutantes en IDH.

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