期刊
CELL DEATH & DISEASE
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2014.294
关键词
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类别
资金
- Ministry of Economy and Competitiveness (MINECO), Spain [BFU2012-35538, ISCIII-RTICC: RD12-0036-0029, SAF2013-43713, BFU2012-33932, SAF2011-25047, CSD2009-00016]
- AGAUR-Generalitat de Catalunya [2009SGR-312]
- People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7) under REA [PITN-GA-2012-316549]
- FPU program (Ministry of Education, Culture and Sport, Spain)
- FPI program (MINECO, Spain) [SAF2011-25047]
Transforming growth factor-beta (TGF-beta) 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-beta in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-beta receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1(-/-) is required for TGF-beta-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-beta, 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-beta-induced survival signals in Cav1(-/-) hepatocytes, such as AKT and ERK1/2 phosphorylation and NF kappa-B activation. Transactivation of the EGFR pathway by TGF-beta 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-beta treatment. In conclusion, in hepatocytes, Cav1(-/-) is required for TGF-J1-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-beta pro-apoptotic effects. Therefore, Cav1(-/-) contributes to the pro-tumorigenic effects of TGF-beta in liver cancer cells.
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