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Los medicamentos de quimioterapia inducen la piroptosis a través de la escisión de la caspasa-3 de una gasdermina
Yupeng Wang1,2, Wenqing Gao1,2, Xuyan Shi1,2
1College of Biological Sciences, China Agricultural University, Beijing 100094, China.
Nature
|May 2, 2017
Resumen
La piroptosis, una forma de muerte celular crucial para la inmunidad, puede ser desencadenada por la caspasa-3 que divide la gasdermina E (GSDME). Esta escisión GSDME cambia la apoptosis a la piroptosis, ofreciendo nuevos conocimientos sobre la quimioterapia del cáncer.
Área de la Ciencia:
- Biología celular
- Inmunología
- Los mecanismos moleculares de la muerte celular
Sus antecedentes:
- La piroptosis es una vía crítica de muerte celular inflamatoria.
- La piroptosis canónica implica la activación de los inflamatorios de la caspasa-1 o de la caspasa-4/5/11.
- La gasdermina D (GSDMD) es el efector conocido, dividido para inducir la piroptosis.
Objetivo del estudio:
- Investigar la función y el mecanismo de activación de otros miembros de la familia de la gasdermina.
- Para explorar el papel de Gasdermin E (GSDME) en la muerte celular.
- Comprender el papel potencial de la GSDME en la respuesta a la quimioterapia.
Principales métodos:
- Se ha investigado la escisión de GSDME por caspase-3.
- Se analizó la piroptosis inducida por GSDME en células cancerosas y células primarias.
- Se utilizaron ratones Gsdme knockout (Gsdme-/-) para evaluar los efectos in vivo.
Principales resultados:
- La gasdermina E (GSDME) fue identificada como un sustrato para la caspasa-3.
- La escisión de la caspasa-3 de GSDME cambia el TNF o la apoptosis inducida por la quimioterapia a la piroptosis.
- Se observó piroptosis dependiente de GSDME en las células cancerosas tratadas con quimioterapia y en las células primarias.
- Los ratones Gsdme-/- mostraron protección contra el daño tisular inducido por la quimioterapia y la pérdida de peso.
Conclusiones:
- La activación de la caspasa-3 puede inducir la piroptosis mediante la escisión de la GSDME, distinta de las vías canónicas.
- La piroptosis mediada por GSDME juega un papel en la respuesta a la quimioterapia y el daño tisular.
- Los hallazgos proporcionan nuevos conocimientos sobre los mecanismos de la quimioterapia contra el cáncer y los posibles objetivos terapéuticos.
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