Una variante de empalme de citrato sintasa vuelve a conectar el ciclo de TCA para promover la progresión del cáncer colorrectal
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Justin Chak Ting Cheung1, Lok Wan Ng2, Zhongxu Zhu3
1Chinese University of Hong Kong, Hong Kong, Hong Kong.
Cancer research
|September 3, 2025
Resumen
Una variante de empalme de citrato sintasa (CS) recientemente descubierta, CS-ΔEx4, impulsa la progresión del cáncer colorrectal (CRC) al alterar el ciclo del ácido tricarboxílico (TCA). Dirigirse a esta variante es prometedor para la terapia de CRC.
Área de la Ciencia:
- Biología del cáncer
- La reprogramación metabólica
- Oncología molecular
Sus antecedentes:
- La reprogramación metabólica, particularmente las alteraciones del ciclo del ácido tricarboxílico (TCA), es una característica clave del cáncer que apoya el crecimiento tumoral y la metástasis.
- Los mecanismos precisos del recableado del ciclo de TCA en la carcinogénesis colorrectal siguen siendo incompletamente entendidos.
Objetivo del estudio:
- Identificar y caracterizar nuevos mecanismos de desregulación del ciclo TCA en el cáncer colorrectal (CRC).
- Investigar el papel de una isoforma de empalme de citrato sintasa (CS) específica, CS-ΔEx4, en la progresión del CRC.
Principales métodos:
- Identificación y cuantificación de las isoformas de splicing CS (CS-ΔEx4 y CS-FL) en los tumores de CCR.
- Análisis de correlación clínica de la expresión de CS-ΔEx4 con los resultados en pacientes.
- Ensayos funcionales in vitro e in vivo para evaluar el papel de CS-ΔEx4 en la agresividad de las células CRC.
- Estudios mecánicos relacionados con la formación de heterocomplejos mitocondriales y el análisis del flujo metabólico.
- En el cribado de silicio para pequeñas moléculas dirigidas al heterocomplejo CS-ΔEx4/CS-FL.
Principales resultados:
- CS-ΔEx4 fue significativamente regulado en tumores de CCR en comparación con la isoforma canónica de CS-FL.
- El aumento de la expresión de CS-ΔEx4 se correlacionó con un aumento de la recurrencia del cáncer y una menor supervivencia en pacientes con CCR.
- CS-ΔEx4 promovió fenotipos agresivos de CRC, aceleró el flujo del ciclo de TCA y aumentó la acumulación de 2-hidroxiglutarato en el oncometabolito.
- Los cambios metabólicos inducidos por CS-ΔEx4 condujeron a alteraciones epigenómicas y al aumento de la regulación de las firmas genéticas oncogénicas.
- Una nueva molécula pequeña inhibió selectivamente el heterocomplejo CS-ΔEx4/CS-FL, mostrando efectos antiproliferativos en modelos de CRC.
Conclusiones:
- Una nueva variante empalmada de la citrato sintasa, CS-ΔEx4, promueve activamente la progresión del cáncer colorrectal.
- CS-ΔEx4 desregula el ciclo de TCA, lo que lleva a la acumulación de oncometabolitos y a la señalización oncogénica.
- La orientación hacia el heterocomplejo CS-ΔEx4/CS-FL representa una estrategia terapéutica potencial para el cáncer colorrectal.
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