Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-B

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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Quintana-Cabrera, R.; Fernández-Fernández, S.; Bobo-Jiménez, V.; Escobar, J.; Sastre, J; Almeida, A.; Bolaños, J.P.
Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis.
Sebastián D*, Hernández-Alvarez MI*, Segalés J*, Sorianello E, Muñoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Oresic M, Pich S, Burcelin R, Palacín M, Zorzano A…
Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation
Josep M. Orellana-Gavaldà, Laura Herrero, Maria Ida Malandrino, Astrid Pañeda, María Sol Rodríguez-Peña, Harald Petry, Guillermina Asins, Sander Van Deventer, Fausto G. Hegardt, Dolors Serra.
A novel GRK2/HDAC6 interaction modulates cell spreading and motility
Vanesa Lafarga, Ivette Aymerich, Olga Tapia, Federico Mayor Jr, Petronila Penela
Regulation of Ribonucleotide Reductase in Response to Iron Deficiency
Nerea Sanvisens, Mari Carmen Bañó, Mingxia Huang y Sergi Puig
Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice
Ainara Cano, Xabier Buqué, Maite Martínez-Uña, Igor Aurrekoetxea, Ariane Menor, Juan Luis García-Rodríguez2, Shelly Lu, José María Mato, Begoña Ochoa y Patricia Aspichueta
Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter
Rubio-Cosials A, Sidow JF, Jiménez-Menéndez N, Fernández-Millán P, Montoya J, Jacobs HT, Coll M, Bernadó P, Solà M.

Intramolecular signal transmission in a tetrameric repressor of the IclR family
Fillet S, Krell T, Morel B, Lu D, Zhang X, Ramos JL.
Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease
Valles-Ortega J*, Duran J*, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Cañas X, Soriano E, Delgado-García JM, Gruart A, Guinovart JJ. * Coautores
Control of Ubp3 ubiquitin protease activity by the Hog1 SAPK modulates transcription upon osmostress
Carme Solé1,3, Mariona Nadal-Ribelles1,3, Claudine Kraft2, Matthias Peter2, Francesc Posas1 and Eulàlia de Nadal1 1. Departament de Ciències Experimentals i de la Salut, Cell Signalling Unit, Universitat Pompeu Fabra (UPF)…
Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice
Natalia Rodríguez-Muela, Francisco Germain, Guillermo Mariño, Patrick S Fitze and Patricia Boya.
Drosophila lipophorin recpetors mediate the uptake of neutral lipids in oocytes and imaginal disc cells by an endocytosis-independent mechanism
Esmeralda Parra-Peralbo y Joaquim Culí
Light-dependent gene regulation by a coenzyme B12-based photoreceptor
Juan Manuel Ortiz-Guerrero, María Carmen Polanco, Francisco J. Murillo, S. Padmanabhan, y Montserrat Elías-Arnanz
Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing
Melo S, Villanueva A, Moutinho C, Davalos V, Spizzo R, Ivan C, Rossi S, Setien F, Casanovas O, Simo-Riudalbas L, Carmona J, Carrere J, Vidal A, Aytes A, Puertas S…
Structure of a Preternary Complex Involving a Prokaryotic NHEJ DNA Polymerase
Nigel C. Brissett*, Maria Jose Martin*, Robert S. Pitcher, Julie Bianchi, Raquel Juarez, Andrew J. Green, Gavin C. Fox, Luis Blanco', and Aidan J. Doherty'. (* coauthors) ('co-corresponding authors)
Crystal structure of the open conformation of the mammalian chaperonin CCT in complex with tubulin
Muñoz IG, Yébenes H, Zhou M, Mesa P, Serna M, Park AY, Bragado-Nilsson E, Beloso A, de Cárcer G, Malumbres M, Robinson CV, Valpuesta JM, Montoya G.
Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase
Manchado E, Guillamot M, de Cárcer G, Eguren M, Trickey M, García-Higuera I, Moreno S, Yamano H, Cañamero M, Malumbres M.

Distributed Biological Computation with Multicellular Engineered Networks
Sergi Regot*, Javier Macia*, Núria Conde, Kentaro Furukawa, Jimmy Kjellén, Tom Peeters, Stefan Hohmann, Eulàlia de Nadal, Francesc Posas* y Ricard Solé*
A Genetic Defect in Exportin-5 Traps Precursor MicroRNAs in the Nucleus of Cancer Cells
Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, Fernandez AF, Davalos V, Villanueva A, Montoya G, Yamamoto H, Schwartz Jr, Esteller M.
Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes
Marta Navarrete and Alfonso Araque
Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain
Marta Nadal, Philippe Mas, Alexandre G. Blanco, Carme Arnan, Maria Solà, Darren J. Hart y Miquel Coll
Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex
F. Javier Pérez-Victoria(1)*, Guillermo Abascal-Palacios(2)*, Igor Tascón(2), Andrey Kajava(3), Javier G. Magadán(1), Erik P. Pioro(4), Juan S. Bonifacino(1), Aitor Hierro(2) *Equal contribution. (1) Cell Biology and Metabolism Program, Eunice Kennedy Shriver National…
Human mitochondrial mTERF wraps around DNA through a left-handed superhelical tandem repeat
Nereida Jiménez-Menéndez1,2, Pablo Fernández-Millán1, Anna Rubio-Cosials1, Carme Arnan1,2, Julio Montoya3, Howard T Jacobs4, Pau Bernadó2, Miquel Coll1,2, Isabel Usón1,5 & Maria Solà1
Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expression
Vanessa Núñeza,1, Daniel Alamedaa,1, Daniel Ricoa,2, Rubén Motab, Pilar Gonzalob, Marta Cedenillaa, Thierry Fischerc, Lisardo Boscád, Christopher K. Glasse, Alicia G. Arroyob, and Mercedes Ricotea,3 Departments of aRegenerative Cardiology and bVascular…
Cysteine string protein-α prevents activity-dependent degeneration in GABAergic synapses
Pablo García-Junco-Clemente , Gloria Cantero ,Leonardo Gómez-Sánchez , Pedro Linares-Clemente, Jose A. Martínez-López , Rafael Luján, Rafael Fernández-Chacón.
A Postincision-Deficient TFIIH Causes Replication Fork Breakage and Uncovers Alternative Rad51- or Pol32-Mediated Restart Mechanisms
María Moriel-Carretero* y Andrés Aguilera* *Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC, Sevilla, Spain
Moonlighting proteins Hal3 and Vhs3 form a heteromeric PPCDC with Ykl088w in yeast CoA biosynthesis
Amparo Ruiz1,4,7, Asier González1,2,7, Ivan Muñoz1,5, Raquel Serrano1,6, J Albert Abrie3, Erick Strauss3 and Joaquín Ariño1,2 1. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain. 2. Institut de Biotecnologia i…

The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm
Weavers*, H., Prieto-Sánchez*, S., Grawe, F., García-López, A.,Artero,R.,F. Wilsch-Braeuninger, M., Ruiz-Gómez, M., Skaer, H. y Delholm, B.
The asymmetric / symmetric activation of GPCR dimers as a possible mechanistic rationale for multiple signalling pathways
Xavier Rovira (1), Jean-Philippe Pin (2) and Jesús Giraldo (1) 1- Laboratory of Systems Pharmacology and Bioinformatics, Institut de Neurociencies and Unitat de Bioestadıstica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain. 2-…
The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1
Herrero-Méndez, A.; Almeida, A.; Fernández, E.; Maestre, C.; Moncada, S.; y Bolaños, J.P.
The mechanism of vault opening from the high resolution structure of the N-terminal repeats of MVP.
Querol-Audí J, Casañas A, Usón I, Luque D, Castón JR, Fita I, Verdaguer N.
Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-B–Induced Cell
Laia Caja, Patricia Sancho, Esther Bertran, Daniel Iglesias-Serret, Joan Gil, Isabel Fabregat
A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function
Sonia A. Melo(1), Santiago Ropero(1), Catia Moutinho(1), Lauri A Aaltonen(2), Hiroyuki Yamamoto(3), George A Calin(4), Simona Rossi(4), Agustin F Fernandez(1), Fatima Carneiro(5), Carla Oliveira(5), Bibiana Ferreira(1), Chang-Gong Liu(4), Alberto Villanueva(6)…
A molecular framework for light and gibberellin control of cell elongation.
Miguel de Lucas1,4, Jean-Michel Davière1,4, Mariana Rodríguez-Falcón1,4, Mariela Pontin1, Juan Manuel Iglesias-Pedraz1, Séverine Lorrain2, Christian Fankhauser2, Miguel Angel Blázquez3, Elena Titarenko1 & Salomé Prat1 Departamento de Genética Molecular de Plantas…