Referencia

Cancer Res 2009; 69: (19). October 1, 2009

Autores

Laia Caja, Patricia Sancho, Esther Bertran, Daniel Iglesias-Serret, Joan Gil, Isabel Fabregat

Resumen

La sobre-activación de la vía MEK/ERK induce resistencia a los efectos pro-apoptóticos del TGF-beta en células tumorales hepáticas, ya que impide la inducción de la expresión de NOX4, una NADPH oxidasa generadora de especies reactivas de oxígeno que juega un papel esencial en el mecanismo mitocondrial de muerte celular mediado por TGF-beta. La inhibición farmacológica, o por medio de siRNAs, de la vía MEK/ERK sensibiliza a las células tumorales hepáticas a los efectos supresores del TGF-beta.

Descripción

Transforming growth factor-beta (TGF-ß) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its pro-apoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-ß in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-ß-induced NOX4 expression is inhibited by anti-apoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the MAPK/ERK pathways. The aim of the present work was to analyze whether resistance to TGF-ß-induced apoptosis in HCC cells is related to impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MEK/ERK pathway in HepG2 cells, which are refractory to the pro-apoptotic effects of TGF-ß, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-ß and PD98059, which correlates with NOX4 up-regulation. Targeting knock-down of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features, by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-ß-induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis.

Imagen artículo Noviembre

(Autores del artículo de izquierda a derecha: Joan Gil, Laia Caja, Patricia Sancho, Esther Bertran, Daniel Iglesias-Serret, Isabel Fabregat) Patricia Sancho es investigadora postdoctoral del programa Sara Borrell del Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación), en el grupo de Isabel Fabregat en el Instituto de Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet, Barcelona.

Descárgate este artículo aquí

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio Fisher Scientific, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

Whi7 is an unstable cell-cycle repressor of the Start transcriptional program

01-10-2017

Start is the main decision point in eukaryotic cell cycle in which cells commit to a new round of cell division. It involves the irreversible activation of a transcriptional program...

Leer más

CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

01-09-2017

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves...

Leer más

Catalytic Cycle of the N-Acetylglucosaminidase NagZ from Pseudomonas aeruginosa

01-08-2017

The N-acetylglucosaminidase NagZ of Pseudomonas aeruginosa catalyzes the first cytoplasmic step in recycling of muropeptides, cell-wall-derived natural products. This reaction regulates gene expression for the β-lactam resistance enzyme, β-lactamase. The...

Leer más

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice.

01-07-2017

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits...

Leer más

Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver

01-06-2017

The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of...

Leer más

Programmed mitophagy is essential for the glycolytic switch during cell differentiation

01-05-2017

Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy...

Leer más

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

01-04-2017

The Bcl-2 (B-cell lymphoma 2) protein Bax (Bcl-2 associated X, apoptosis regulator) can commit cells to apoptosis via outer mitochondrial membrane permeabilization. Bax activity is controlled in healthy cells by...

Leer más

Histone chaperone activity of Arabidopsis thaliana NRP1 is blocked by cytochrome c

01-03-2017

Higher-order plants and mammals use similar mechanisms to repair and tolerate oxidative DNA damage. Most studies on the DNA repair process have focused on yeast and mammals, in which histone...

Leer más

The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes

01-02-2017

The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty...

Leer más

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

01-01-2017

Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences...

Leer más

Socios Protectores