Laia Caja

Science for Life Laboratory

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Isabel Fabregat

Institut d'Investigació Biomédica de Bellvitge

Patricia Sancho

Hospital Universitario Miguel Servet

Aristidis Moustakas

Science for Life Laboratory

Esther Bertrán

Institut d'Investigació Biomédica de Bellvitge

Daniel Iglesias‐Serret

Universitat de Barcelona

Carl‐Henrik Heldin

Uppsala University

Joan Gil

Universitat de Barcelona

Mahsa Shahidi Dadras

Weill Cornell Medicine

Anita Morén

Science for Life Laboratory

Claudia Bellomo

Federico II University Hospital

Cooperative Institutions

Uppsala University

Science for Life Laboratory

Universitat de Barcelona

Institut d'Investigació Biomédica de Bellvitge

Bellvitge University Hospital

Ludwig Cancer Research

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Karolinska Institutet

Instituto de Salud Carlos III

Consejo Superior de Investigaciones Científicas

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CCDC 964851: Experimental Crystal Structure Determination

The Cambridge Structural Database (2014)

Alba Pérez‐Perarnau Sara Preciado Claudia Mariela Palmeri Cristina Moncunill‐Massaguer Daniel Iglesias‐Serret

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Crystal (programming language)

10.5517/cc11d07p

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Caveolin-1 is required for TGF- β -induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17

Cell Death and Disease (2014)

Joaquim Moreno‐Càceres Laia Caja Jèssica Mainez Rafael Mayoral Paloma Martín‐Sanz

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1−/− hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1−/− hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1−/− hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1−/− hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1+/+ cells, which was not the case in Cav1−/− cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells.

Caveolin 1

10.1038/cddis.2014.294

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Snail: in the cross-roads among EMT and apoptosis

Jèssica Mainez Diana L. Franco Sonia Vega Patricia Sancho Miguel Murillo

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Role of CXCR4/SDF-1α in the migratory phenotype of hepatoma cells that have undergone epithelial–mesenchymal transition in response to the transforming growth factor-β

Cellular Signalling (2009)

Esther Bertrán Laia Caja Estanis Navarro Patricia Sancho Jèssica Mainez

10.1016/j.cellsig.2009.06.006

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Citations (70)

Supplementary Figures 1-6 from Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

Laia Caja Patricia Sancho Esther Bertrán Daniel Iglesias‐Serret Joan Gil

Supplementary Figures 1-6 from Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

NOX4

10.1158/0008-5472.22382001

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Data from Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

Laia Caja Patricia Sancho Esther Bertrán Daniel Iglesias‐Serret Joan Gil

<div>Abstract<p>Transforming growth factor-β (TGF-β) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-β in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-β–induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-β–induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-β, 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-β and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown 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-β–induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis. [Cancer Res 2009;69(19):7595–602]</p></div>

NOX4

10.1158/0008-5472.c.6500061.v1

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Transforming growth factor β as regulator of cancer stemness and metastasis

British Journal of Cancer (2016)

Claudia Bellomo Laia Caja Aristidis Moustakas

Key elements of cancer progression towards metastasis are the biological actions of cancer stem cells and stromal cells in the tumour microenvironment. Cross-communication between tumour and stromal cells is mediated by secreted cytokines, one of which, the transforming growth factor β (TGFβ), regulates essentially every cell within the malignant tissue. In this article, we focus on the actions of TGFβ on cancer stem cells, cancer-associated fibroblasts and immune cells that assist the overall process of metastatic dissemination. We aim at illustrating intricate connections made by various cells in the tumour tissue and which depend on the action of TGFβ.

10.1038/bjc.2016.255

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A Trifluorinated Thiazoline Scaffold Leading to Pro‐apoptotic Agents Targeting Prohibitins

Angewandte Chemie International Edition (2014)

Alba Pérez‐Perarnau Sara Preciado Claudia Mariela Palmeri Cristina Moncunill‐Massaguer Daniel Iglesias‐Serret

Abstract A new class of small molecules, with an unprecedented trifluorothiazoline scaffold, were synthesized and their pro‐apoptotic activity was evaluated. With an EC 50 in the low micromolar range, these compounds proved to be potent inducers of apoptosis in a broad spectrum of tumor cell lines, regardless of the functional status of p53. Fast structure–activity relationship studies allowed the preparation of the strongest apoptosis‐inducing candidate. Using a high performance affinity purification approach, we identified prohibitins 1 and 2, key proteins involved in the maintenance of cell viability, as the targets for these compounds.

Thiazoline

Viability assay

10.1002/anie.201405758

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Citations (38)

Supplementary Figure Legends 1-6 from Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

Laia Caja Patricia Sancho Esther Bertrán Daniel Iglesias‐Serret Joan Gil

NOX4

10.1158/0008-5472.22382004

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The liver kinase B1 supports mammary epithelial morphogenesis by inhibiting critical factors that mediate epithelial‐mesenchymal transition

Journal of Cellular Physiology (2023)

Kalliopi Tzavlaki Yae Ohata Anita Morén Yukihide Watanabe Jens Eriksson

Abstract The liver kinase B1 (LKB1) controls cellular metabolism and cell polarity across species. We previously established a mechanism for negative regulation of transforming growth factor β (TGFβ) signaling by LKB1. The impact of this mechanism in the context of epithelial polarity and morphogenesis remains unknown. After demonstrating that human mammary tissue expresses robust LKB1 protein levels, whereas invasive breast cancer exhibits significantly reduced LKB1 levels, we focused on mammary morphogenesis studies in three dimensional (3D) acinar organoids. CRISPR/Cas9‐introduced loss‐of‐function mutations of STK11 ( LKB1 ) led to profound defects in the formation of 3D organoids, resulting in amorphous outgrowth and loss of rotation of young organoids embedded in matrigel. This defect was associated with an enhanced signaling by TGFβ, including TGFβ auto‐induction and induction of transcription factors that mediate epithelial‐mesenchymal transition (EMT). Protein marker analysis confirmed a more efficient EMT response to TGFβ signaling in LKB1 knockout cells. Accordingly, chemical inhibition of the TGFβ type I receptor kinase largely restored the morphogenetic defect of LKB1 knockout cells. Similarly, chemical inhibition of the bone morphogenetic protein pathway or the TANK‐binding kinase 1, or genetic silencing of the EMT factor SNAI1, partially restored the LKB1 knockout defect. Thus, LKB1 sustains mammary epithelial morphogenesis by limiting pathways that promote EMT. The observed downregulation of LKB1 expression in breast cancer is therefore predicted to associate with enhanced EMT induced by SNAI1 and TGFβ family members.

SNAI1

10.1002/jcp.30975

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