SEBBM - Sociedad Española de Bioquímica y Biología Molecular

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.

(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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