Nature Medicine 18, 892–901 (2012) // doi:10.1038/nm.2772


Stephan P Tenbaum, Paloma Ordóñez-Morán, Isabel Puig, Irene Chicote, Oriol Arqués, Stefania Landolfi, Yolanda Fernández, José Raúl Herance, Juan D Gispert, Leire Mendizabal, Susana Aguilar, Santiago Ramón y Cajal, Simó Schwartz Jr, Ana Vivancos, Eloy Espín, Santiago Rojas, José Baselga, Josep Tabernero, Alberto Muñoz & Héctor G Palmer


The Wnt-β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt-β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear β-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt-β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it behave as a metastasis inductor rather than a proapoptotic tumor suppressor. We show that it is possible to evaluate the β-catenin status of patients' carcinomas and the response of patient-derived cells to target-directed drugs that accumulate FOXO3a in the nucleus before deciding on a course of treatment. We propose that this evaluation could be essential to the provision of a safer and more effective personalized treatment.


Las vías de señalización oncogénicas de PI3K/AKT y de Wnt/β-catenina se encuentran alteradas genéticamente en un gran número de tumores de colon humano. La activación aberrante de la vía PI3K/AKT elimina la actividad supresora tumoral del factor de trascripción FOXO3a mientras la activación de la vía Wnt/ β-catenina promueve entre otras cosas el crecimiento del tumor. La inhibición farmacológica de estas vías, supone por lo tanto una estrategia muy tentadora de terapia anti-tumoral ya que promueve la muerte de las células tumorales por la acción de FOXO3a. Actualmente existen varios inhibidores de PI3K y AKT que se están usando en ensayos clínicos. Estudiando la interacción de las proteínas FOXO3a y β-catenina pudimos demostrar que la inhibición de PI3K o AKT en presencia de altos niveles nucleares de β-catenina promovía el efecto contrario al esperado. Las células cancerosas, en vez de morir por el tratamiento, se volvían resistentes y contribuían a la formación de metástasis. La determinación de los niveles de β-catenina nuclear, como biomarcador, en los tumores de colon antes de iniciar el tratamiento, permite por lo tanto predecir la respuesta a los fármacos inhibidores de la vía PI3K/AKT.

imagen agosto


El grupo de Células Madre y Cáncer del VHIO está investigando los mecanismos moleculares del cáncer que son relevantes para la supervivencia de los pacientes. Entre ellos se encuentran los procesos que permiten a los tumores resistir las terapias, reaparecer y metastatizar. El cáncer de colon es una patología con gran impacto social y por eso está en el foco de nuestras investigaciones. En particular, estamos analizando la heterogeneidad celular intra-tumoral, especialmente el papel de las células madre cancerosas que parecen ser responsables de los procesos mencionados. A nivel molecular estudiamos las vías de señalización oncogénicas que controlan la función de las células madre cancerosas, como es el caso de las vías de PI3K/AKT y de Wnt/ β-catenina.

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