Hypoxia-mediated alterations and their role in the HER-2/neuregulated CREB status and localization
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André Steven1, Sandra Leisz1, Katharina Sychra6, Bernhard Hiebl2, Claudia Wickenhauser3, Dimitrios Mougiakakos4, Rolf Kiessling5, Carsten Denkert6, Barbara Seliger1
1Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
2Centre for Basic Medical Research, Martin Luther University Halle-Wittenberg, Halle, Germany
3Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle, Germany
4Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
5Karolinska Institutet, CCK, Stockholm, Sweden
6Charité, Institute of Pathology, Berlin, Germany
Barbara Seliger, email: [email protected]
Keywords: CREB, HER-2/neu, hypoxia, angiogenesis, mitochondria
Received: March 11, 2016 Accepted: June 17, 2016 Published: July 7, 2016
The cAMP-responsive element-binding protein (CREB) is involved in the tumorigenicity of HER-2/neu-overexpressing murine and human tumor cells, but a link between the HER-2/neu-mediated CREB activation, its posttranslational modification and localization and changes in the cellular metabolism, due to an altered (tumor) microenvironment remains to be established. The present study demonstrated that shRNA-mediated silencing of CREB in HER-2/neu-transformed cells resulted in decreased tumor formation, which was associated with reduced angiogenesis, but increased necrotic and hypoxic areas in the tumor. Hypoxia induced pCREBSer133, but not pCREBSer121 expression in HER-2/neu-transformed cells. This was accompanied by upregulation of the hypoxia-inducible genes GLUT1 and VEGF, increased cell migration and matrix metalloproteinase-mediated invasion. Treatment of HER-2/neu+ cells with signal transduction inhibitors targeting in particular HER-2/neu was able to revert hypoxia-controlled CREB activation. In addition to changes in the phosphorylation, hypoxic response of HER-2/neu+ cells caused a transient ubiquitination and SUMOylation as well as a co-localization of nuclear CREB to the mitochondrial matrix. A mitochondrial localization of CREB was also demonstrated in hypoxic areas of HER-2/neu+ mammary carcinoma lesions. This was accompanied by an altered gene expression pattern, activity and metabolism of mitochondria leading to an increased respiratory rate, oxidative phosphorylation and mitochondrial membrane potential and consequently to an enhanced apoptosis and reduced cell viability. These data suggest that the HER-2/neu-mediated CREB activation caused by a hypoxic tumor microenvironment contributes to the neoplastic phenotype of HER-2/neu+ cells at various levels.
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