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.

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