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 al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity

01-07-2020

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. A-to-I editing of RNA is a widespread posttranscriptional process that has recently emerged as an important mechanism...

Leer más

Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in Drosophila

29-05-2020

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca2+ peak that triggers muscle contraction, but mechanistic details remain unknown...

Leer más

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

30-04-2020

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the...

Leer más

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

31-03-2020

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT 178R ↓S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3...

Leer más

Identification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis

29-02-2020

Technical problems intrinsic to the purification of preribosome intermediates have limited our understanding of ribosome biosynthesis in humans. Addressing this issue is important given the implication of this biological process...

Leer más

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

23-01-2020

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of...

Leer más

Mip6 binds directly to the Mex67 UBA domain to maintain low levels of Msn2/4 stress-dependent mRNAs

23-12-2019

RNA-binding proteins (RBPs) participate in all steps of gene expression, underscoring their potential as regulators of RNA homeostasis. We structurally and functionally characterize Mip6, a four-RNA recognition motif (RRM)-containing RBP...

Leer más

A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis

01-12-2019

Plasmalogens are glycerophospholipids with a hallmark sn-1 vinyl ether bond. These lipids are found in animals and some bacteria and have proposed membrane organization, signaling, and antioxidant roles. We discovered...

Leer más

The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

01-11-2019

Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper...

Leer más

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

01-10-2019

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...

Leer más

Socios Protectores