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Muerte celular oxidativa dependiente de RAS-RAF-MEK que involucra canales aniónicos dependientes de voltaje
Nicholas Yagoda1, Moritz von Rechenberg, Elma Zaganjor
1Department of Biological Sciences, Fairchild Center, 1212 Amsterdam Avenue, MC 2406, New York, New York 10027, USA.
Nature
|June 15, 2007
Resumen
Erastin mata selectivamente las células cancerosas con mutaciones en la vía RAS-RAF-MEK al atacar las proteínas VDAC mitocondriales, induciendo el estrés oxidativo y la muerte celular no apoptótica. Esto revela los VDAC como nuevos objetivos de fármacos anticancerígenos.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Oncología Oncología.
- La bioquímica es la bioquímica.
Sus antecedentes:
- Las terapias dirigidas contra el cáncer requieren agentes que discriminen entre las células normales y las tumorales.
- La letalidad oncogénica selectiva ofrece una estrategia para desarrollar fármacos contra el cáncer más efectivos y menos tóxicos.
- La vía de señalización RAS-RAF-MEK es crucial para la proliferación celular, la diferenciación y la supervivencia, y con frecuencia se muta en los cánceres.
Objetivo del estudio:
- Para dilucidar el mecanismo de acción del agente antitumoral selectivo erastin.
- Para identificar nuevos objetivos moleculares para la terapéutica del cáncer.
- Investigar el papel de la vía RAS-RAF-MEK en la actividad anticancerígena de la erastina.
Principales métodos:
- Purificación de afinidad y espectrometría de masas para identificar los socios de unión de la erastina.
- Los ensayos de viabilidad celular evalúan la letalidad de la erastina en células cancerosas con mutaciones oncogénicas específicas.
- Interferencia de ARN para investigar el papel de las isoformas de VDAC.
- Pruebas de permeabilidad mitocondrial.
- Ensayos de unión de filtros con erastina radiomarcada.
Principales resultados:
- Erastin exhibe letalidad selectiva hacia las células tumorales humanas con mutaciones HRAS, KRAS o BRAF.
- Erastin tiene como objetivo los canales aniónicos mitocondriales dependientes de la tensión (VDAC).
- Erastin induce especies oxidativas y muerte celular no apoptótica en las células oncogénicas que expresan RAS.
- La eliminación de VDAC2 y VDAC3 confiere resistencia a la erastina.
- Erastin altera la permeabilidad de la membrana mitocondrial externa y se une directamente al VDAC2.2.
Conclusiones:
- Las funciones de Erastin apuntan a las proteínas VDAC, un nuevo mecanismo para los medicamentos contra el cáncer.
- Los ligandos dirigidos a las proteínas VDAC pueden inducir la muerte celular no apoptótica selectiva en tumores con mutaciones activadoras en la vía RAS-RAF-MEK.
- Este estudio identifica a los VDAC como objetivos prometedores para el desarrollo de nuevas terapias selectivas contra el cáncer.
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