Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells

Caja, Laia; Sancho, Patricia; Bertrán, Esther; Fabregat, Isabel

doi:10.1016/j.jhep.2010.10.041

Cited by 49 publications

(66 citation statements)

References 39 publications

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“…4, 18 We hypothesized that EGFR transactivation by TGF- β could be perturbed in the absence of Cav1. In Cav1 +/+ cells, TGF- β induced phosphorylation of EGFR, examined both by western blot (Figure 3a) and immunocytochemistry (Figure 3b).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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“…We and others have described previously that suppressor functions of TGF-␤ in hepatocytes, mainly growth inhibition and apoptosis induction, can be inhibited by different survival signals through activation of the EGFR, PI3K/AKT, and/or ERK1/2 hyperactivation (26 -28) that are frequently observed in tumoral hepatocytes (18,19). In most cases, such prosurvival signals are dependent on growth factor or cytokine receptors, whose activation status is controlled mainly by phosphorylation/dephosphorylation cycles triggered by protein kinases and phosphatases.…”

Section: Discussionmentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Ortiz

Caja

Bertrán

et al. 2012

Journal of Biological Chemistry

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Background: Tyrosine kinases and phosphatases modulate TGF-␤ signaling. Results: PTP1B deficiency attenuates TGF-␤-induced Smad phosphorylation correlating with suppression of growth inhibition and apoptosis, an effect that is reverted by genistein, and p65 or NOX1 knockdown. Conclusion: Lack of PTP1B impairs Smad activation in a NOX1 and NF-B-dependent manner. Significance: New insights are opened into the role of phosphatases in TGF-␤ signaling.

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“…We first tested whether cultured Marfan VSMC also showed the overactivation of TGF-β signaling pathway seen in human aortic aneurysms (Figure 1). We observed (1) enhanced by guest on May 7, 2018 http://atvb.ahajournals.org/ Downloaded from basal pSMAD2 and pSMAD3 protein levels ( Figure 4A) and nuclear accumulation of both pSMADs ( Figure 4B); and (2) increased total TGF-β levels in the extracellular medium (conditioned medium; Figure 4C), which in turn increased the pSMAD2 signal response in hepatocarcinoma Hep3B cell line 28 ( Figure 4D). Moreover, the previous incubation of conditioned media with a neutralizing anti-TGF-β antibody, which was subsequently added to Hep3B cells to evaluate the nuclear translocation of SMAD2, indicated that Marfanconditioned medium contained more active TGF-β than that We next measured the expression of the aforementioned phenotypic markers.…”

Section: Human Marfan Aortic Aneurysms Overexpress Both Contractile Amentioning

confidence: 89%

“…In any case, we cannot rule out that myocardin may also act independently of SRF. 50 Therefore, myocardin seems as one of the main TGF-β by guest on May 7, 2018 http://atvb.ahajournals.org/ Downloaded from targets that trigger the overexpression of contractile proteins in Marfan VSMC. Interestingly, contractile protein upregulation occurs in parallel to (and not in contraposition to) that of collagen I.…”

Section: Pathophysiological Significance Of Phenotypic Changes Of Vsmmentioning

confidence: 99%

Vascular Smooth Muscle Cell Phenotypic Changes in Patients With Marfan Syndrome

Crosas‐Molist

Meirelles

López-Luque

et al. 2015

ATVB

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124

119

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Objective— Marfan’s syndrome is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix microfibrils and chronic tissue growth factor (TGF)-β signaling. TGF-β is a potent regulator of the vascular smooth muscle cell (VSMC) phenotype. We hypothesized that as a result of the chronic TGF-β signaling, VSMC would alter their basal differentiation phenotype, which could facilitate the formation of aneurysms. This study explores whether Marfan’s syndrome entails phenotypic alterations of VSMC and possible mechanisms at the subcellular level. Approach and Results— Immunohistochemical and Western blotting analyses of dilated aortas from Marfan patients showed overexpression of contractile protein markers (α-smooth muscle actin, smoothelin, smooth muscle protein 22 alpha, and calponin-1) and collagen I in comparison with healthy aortas. VSMC explanted from Marfan aortic aneurysms showed increased in vitro expression of these phenotypic markers and also of myocardin, a transcription factor essential for VSMC-specific differentiation. These alterations were generally reduced after pharmacological inhibition of the TGF-β pathway. Marfan VSMC in culture showed more robust actin stress fibers and enhanced RhoA-GTP levels, which was accompanied by increased focal adhesion components and higher nuclear localization of myosin-related transcription factor A. Marfan VSMC and extracellular matrix measured by atomic force microscopy were both stiffer than their respective controls. Conclusions— In Marfan VSMC, both in tissue and in culture, there are variable TGF-β-dependent phenotypic changes affecting contractile proteins and collagen I, leading to greater cellular and extracellular matrix stiffness. Altogether, these alterations may contribute to the known aortic rigidity that precedes or accompanies Marfan’s syndrome aneurysm formation.

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Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells

Cited by 49 publications

References 39 publications

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

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

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Vascular Smooth Muscle Cell Phenotypic Changes in Patients With Marfan Syndrome

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