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Chk1 suprime una respuesta apoptótica de la caspasa-2 al daño del ADN que elude p53, Bcl-2 y la caspasa-3

Samuel Sidi¹, Takaomi Sanda, Richard D Kennedy

¹Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

|May 31, 2008

Resumen

La inhibición de la quinasa del punto de control 1 (Chk1) restaura la muerte celular inducida por el daño del ADN en las células cancerosas mediante la activación de una vía apoptótica alternativa. Esta vía suprimida por Chk1 evita las mutaciones de p53 y la sobreexpresión de Bcl-2, ofreciendo nuevas estrategias terapéuticas.

Área de la Ciencia:

Biología Molecular Biología Molecular
Biología celular Biología celular.
Investigación del cáncer Investigación del cáncer.

Sus antecedentes:

Las células cancerosas evaden la apoptosis a través de mutaciones p53 o sobreexpresión de proteínas de la familia Bcl-2, lo que lleva a la transformación maligna y la resistencia terapéutica.
La quinasa de punto de control 1 (Chk1) juega un papel crítico en la respuesta al daño del ADN, y su inhibición se está explorando como una estrategia de terapia contra el cáncer.

Objetivo del estudio:

Investigar el mecanismo por el cual la inhibición de Chk1 restaura la apoptosis inducida por daño al ADN en las células cancerosas.
Identificar los actores moleculares clave y las vías involucradas en la muerte celular mediada por inhibidores de Chk1.

Principales métodos:

Se utilizaron embriones de pez cebra con mutaciones p53 y líneas de células tumorales humanas.
Empleó radiación gamma para inducir daño en el ADN.
Se evaluó la apoptosis, la fragmentación del ADN y la activación de las caspasas (caspasa-3, caspasa-2) y las quinasas (ATM, ATR).
Investigó el papel de las proteínas de las familias p53 y Bcl-2 en el proceso apoptótico.

Principales resultados:

El agotamiento o la inhibición de Chk1 restauró la apoptosis inducida por radiación gamma en embriones de pez cebra mutantes p53.
Se identificó un nuevo programa apoptótico, independiente de la activación de la caspasa-3.
Esta vía alternativa requiere ATM, ATR y caspase-2, y no se ve afectada por la pérdida de p53 o la sobreexpresión de Bcl-2/xl.
Las células tumorales humanas tratadas con inhibidores de Chk1 activaron ATM, ATR y caspase-2, lo que condujo a una apoptosis dependiente de la caspase-2 que evitó la deficiencia de p53 y el exceso de Bcl-2.

Conclusiones:

La vía "Chk1-suprimida" evolucionariamente conservada representa un nuevo proceso apoptótico.
Esta vía responde a los inhibidores de Chk1 y es insensible a las alteraciones en p53 y Bcl-2.
Dirigirse a Chk1 ofrece una estrategia terapéutica prometedora para los cánceres con defectos en la regulación de la apoptosis, independientemente del estado de p53 o Bcl-2.

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