Referencia

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

Autores

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

Resumen

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.

Descripción

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

REFERENCIA DEL GRUPO INVESTIGADOR

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.

Más artículos en la revista SEBBM.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

15-10-2019

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create...

Read more

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Read more

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Read more

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Read more

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Read more

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Read more

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Read more

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Read more

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Read more

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Read more

Protector Members