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Las sulfonamidas anticancerígenas se dirigen al empalme induciendo la degradación de RBM39 a través del reclutamiento
Ting Han1, Maria Goralski2, Nicholas Gaskill2
1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science (New York, N.Y.)
|March 18, 2017
Resumen
El fármaco anticancerígeno Indisulam se dirige a la proteína 39 del motivo de unión al ARN (RBM39) para su degradación a través del complejo CUL4-DCAF15, afectando el splicing pre- ARNm. Los niveles de expresión de DCAF15 se correlacionan con la sensibilidad de las células cancerosas al indisulam y a los fármacos SPLAM relacionados.
Área de la Ciencia:
- En el campo de la oncología
- Biología molecular
- Farmacología
Sus antecedentes:
- Indisulam es una sulfamida de arilo con actividad anticancerígena selectiva.
- El mecanismo preciso de acción y la base de selectividad de indisulam eran desconocidos.
Objetivo del estudio:
- Elucidar el mecanismo molecular subyacente a la actividad y la selectividad anticancerígenas del indisulam.
- Identificar potenciales biomarcadores para predecir la respuesta del paciente al indisulam y medicamentos relacionados.
Principales métodos:
- Se investigó la interacción de indisulam con las proteínas celulares mediante ensayos bioquímicos.
- Se analizó el efecto del indisulam en la ubiquitinación y degradación del RBM39.
- Se evaluó el impacto de indisulam en el empalme del pre- ARNm en las líneas celulares cancerosas.
- Sensibilidad al fármaco correlacionada con los niveles de expresión de DCAF15 en varios tipos de células cancerosas.
Principales resultados:
- El indisulam promueve el reclutamiento de la proteína 39 del motivo de unión al ARN (RBM39) a la ubiquitina ligasa CUL4-DCAF15 E3.
- Este reclutamiento conduce a la poliubiquitinación de RBM39 y la degradación proteasómica, causando un empalme aberrante del pre-ARNm.
- Las mutaciones que impiden el reclutamiento de RBM39 confieren resistencia al indisulam.
- La sensibilidad al indisulam en las líneas celulares de cáncer hematopoyético y linfoide se correlaciona con la expresión de DCAF15.
Conclusiones:
- El indisulam funciona dirigiéndose a RBM39 para su degradación a través del complejo CUL4-DCAF15, interrumpiendo el splicing pre-mRNA.
- La expresión de DCAF15 sirve como un biomarcador predictivo potencial para las SPLAM (sulfonamidas inhibidoras de empalme), incluidos el indisulam, el tasisulam y la sulfonamida de cloroquinoxalina.
- Este hallazgo ofrece una base para guiar los ensayos clínicos y la selección de pacientes para terapias basadas en SPLAM.
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