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La liberación subletal del citocromo c genera células persistentes tolerantes al fármaco
Halime Kalkavan1, Mark J Chen1, Jeremy C Crawford1
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell
|September 2, 2022
Resumen
Las células persistentes tolerantes a los medicamentos evaden el tratamiento del cáncer. El daño mitocondrial subletal y la liberación del citocromo c desencadenan una respuesta al estrés, creando estas células persistentes, que son vulnerables a la ferroposis.
Área de la Ciencia:
- Biología celular
- Investigación del cáncer
- Oncología molecular
Sus antecedentes:
- Las células persistentes tolerantes a los medicamentos (persistentes) son un obstáculo significativo en el tratamiento del cáncer, evitando la apoptosis inducida por las terapias.
- Comprender los mecanismos detrás de la formación de células persistentes es crucial para desarrollar terapias más efectivas contra el cáncer.
Objetivo del estudio:
- Investigar los mecanismos moleculares subyacentes a la generación de células persistentes tolerantes a los medicamentos.
- Identificar las vías de señalización clave involucradas en la supervivencia celular persistente y sus vulnerabilidades.
Principales métodos:
- Utilizó imitaciones pro-apoptóticas de BH3 para inducir la formación de células persistentes en modelos de cáncer.
- Se ha investigado la permeabilización de la membrana externa mitocondrial (MOMP) y la liberación del citocromo c.
- Analizó las funciones de la respuesta integrada al estrés (ISR), la inhibidor regulado por hemo (HRI) quinasa y ATF4 en la generación de células persistentes.
Principales resultados:
- Las células que sobrevivieron al tratamiento mimético BH3 mostraron un fenotipo persistente, incluyendo colonización in vivo y metástasis.
- La MOMP subletal y la liberación de holocitocromo c fueron esenciales para la generación de células persistentes.
- La generación de células persistentes fue independiente de la activación del apoptosoma y la caspasa, pero requirió citocromo c citosólico, HRI quinasa, ISR y ATF4.
Conclusiones:
- La liberación subletal del citocromo c vincula el MOMP subletal con la activación ATF4 independiente de la caspasa, estableciendo un fenotipo persistente tolerante al fármaco.
- Las células persistentes muestran una mayor sensibilidad a la inducción de ferroptosis a través de la inhibición de GPX4.
- Estos hallazgos revelan una nueva vía para la generación de células persistentes y sugieren posibles estrategias terapéuticas dirigidas a este mecanismo.
Palabras clave:
ATF4 para el transporte de mercancíasFamilia Bcl-2GPX4 y sus derivadosHRI y sus derivadosLa ferroposisRespuesta integrada al estrés persistenteMás Videos Relacionados
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