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La deubiquitinasa USP9X estabiliza el MCL1 y promueve la supervivencia de las células tumorales
Martin Schwickart1, Xiaodong Huang, Jennie R Lill
1Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature
|December 22, 2009
Resumen
La deubiquitinasa USP9X estabiliza MCL1, una proteína crucial para la supervivencia de las células cancerosas. La inhibición de USP9X puede ofrecer una nueva estrategia terapéutica para el tratamiento de ciertos tipos de cáncer como el linfoma y el mieloma múltiple.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- MCL1 es vital para la supervivencia de las células madre y progenitoras, pero se degrada rápidamente.
- La sobreexpresión anormal de MCL1 en los linfomas y la leucemia contribuye a la quimiorresistencia y la recaída.
- Los mecanismos que impulsan la sobreexpresión de MCL1 en el cáncer siguen siendo en gran medida poco claros.
Objetivo del estudio:
- Investigar el papel de USP9X en la regulación de la estabilidad de la proteína MCL1.
- Para determinar si USP9X es un objetivo terapéutico potencial en las neoplasias malignas dependientes de MCL1.
Principales métodos:
- Investigó la interacción entre USP9X y MCL1.1.
- Se analizó el efecto de USP9X en la ubiquitinación de MCL1 y la degradación proteasómica.
- Expresión correlacionada de USP9X con niveles de MCL1 y pronóstico del paciente en muestras de linfoma humano y mieloma múltiple.
- Se examinó el impacto de la eliminación de USP9X en la sensibilidad de las células cancerosas al ABT-737, un imitador de BH3.
Principales resultados:
- USP9X se une directamente a MCL1 y elimina las cadenas de ubiquitina que marcan la degradación, estabilizando así MCL1.
- La expresión elevada de USP9X se correlaciona con el aumento de los niveles de proteína MCL1 en los linfomas foliculares y los linfomas difusos de células B grandes.
- Una alta expresión de USP9X en pacientes con mieloma múltiple indica un mal pronóstico.
- La eliminación de USP9X conduce a un aumento de la ubiquitinación de MCL1, una mayor degradación y un aumento de la muerte de las células cancerosas tras el tratamiento con ABT-737.
Conclusiones:
- USP9X estabiliza MCL1, promoviendo la supervivencia de las células cancerosas y contribuyendo al mal pronóstico en el mieloma múltiple.
- USP9X representa un nuevo objetivo prognóstico y terapéutico para los cánceres dependientes de MCL1.
- Las deubiquitinasas pueden estabilizar las oncoproteínas labiles, destacando su papel en el desarrollo y la progresión del cáncer.
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