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Las interacciones entre los macrófagos y las células cancerosas median la resistencia hormonal a través de una vía de

Ping Zhu¹, Sung Hee Baek, Eliot M Bourk

¹Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.

|February 14, 2006

Resumen

Las células de cáncer de próstata y los macrófagos desencadenan antagonistas / moduladores selectivos del receptor de andrógenos (SARM) para activar la expresión génica. Este interruptor implica un motivo conservado, TAB2, y señales inflamatorias, que vinculan las funciones reproductivas con las respuestas de los receptores nucleares.

Área de la Ciencia:

Biología molecular La biología molecular.
Endocrinología Endocrinología.
Investigación del cáncer investigación del cáncer.

Sus antecedentes:

Comprender la regulación transcripcional es clave para el desarrollo, la homeostasis y los cánceres dependientes de las hormonas.
Los antagonistas / moduladores selectivos de los receptores de andrógenos (SARM) son cruciales en el manejo del cáncer de próstata.

Objetivo del estudio:

Para dilucidar los mecanismos moleculares detrás del interruptor en la función SARM de la represión a la activación.
Para investigar el papel de las interacciones entre las células del cáncer de próstata y los macrófagos en este interruptor funcional.

Principales métodos:

Investigó motivos L/HX7LL conservados en el N-terminal en los receptores de esteroides sexuales.
Estudió el reclutamiento de TAB2 a los complejos corepresores N-CoR.
Se examinó el papel de las señales inflamatorias, MEKK1 y la eliminación del complejo N-CoR/HDAC.

Principales resultados:

Descubrió que las interacciones específicas entre las células del cáncer de próstata y los macrófagos cambian la función SARM de represión a activación.
Se identificó un motivo L/HX7LL conservado que media en el reclutamiento de TAB2 a N-CoR.
Se demostró que TAB2 detecta señales inflamatorias, reclutando MEKK1 para descartar N-CoR / HDAC, lo que lleva a la desrepresión de los genes diana de los receptores de andrógenos y estrógenos.

Conclusiones:

Un mecanismo de sensores conservado enlaza las respuestas de los ligandos de los receptores inflamatorios y nucleares.
Este mecanismo invierte la represión dependiente de los esteroides sexuales de los genes diana en respuesta a la inflamación.
Los hallazgos conectan las vías de señalización inflamatoria con la función del receptor nuclear en la biología reproductiva y el cáncer.

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