Linking CREB function with altered metabolism in murine fibroblast-based model cell lines
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André Steven1, Sandra Leisz1, Claudia Wickenhauser2, Kristin Schulz1, Dimitrios Mougiakakos3, Rolf Kiessling4, Carsten Denkert5 and Barbara Seliger1
1Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
2Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle, Germany
3Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
4Karolinska Institute, CCK, Stockholm, Sweden
5Charité Berlin, Institute of Pathology, Berlin, Germany
Barbara Seliger, email: [email protected]
Keywords: CREB; HER-2/neu; metabolism; mitochondria; ROS
Received: February 23, 2017 Accepted: August 26, 2017 Published: October 27, 2017
The cAMP-responsive element binding protein CREB is frequently overexpressed and activated in tumors of distinct histology, leading to enhanced proliferation, migration, invasion and angiogenesis as well as reduced apoptosis. The de-regulated expression of CREB might be linked with transcriptional as well as post-transcriptional regulation mechanisms. We show here that altered CREB expression levels and function are associated with changes in the cellular metabolism. Using comparative proteome-based analysis an altered expression pattern of proteins involved in the cellular metabolism in particular in glycolysis was found upon CREB down-regulation in HER-2/neu-transfected cell lines. This was associated with diminished expression levels of the glucose transporter 1, reduced glucose uptake and reduced glycolytic activity in HER-2/neu-transfected cells with down-regulated CREB when compared to HER-2/neu+ cells. Furthermore, hypoxia-induced CREB activity resulted in changes of the metabolism in HER-2/neu transfected cells. Low pH values in the supernatant of HER-2/neu transformants were restored by CREB down-regulation, but further decreased by hypoxia. The altered intracellular pH values were associated with a distinct expression of lactate dehydrogenase, and its substrate lactate. Moreover, enhanced phosphorylation of CREB on residue Ser133 was accompanied by a down-regulation of pERK and an up-regulation of pAKT. CREB promotes the detoxification of ROS by catalase, therefore protecting the mitochondrial activity under oxidative stress. These data suggest that there might exists a link between CREB function and the altered metabolism in HER-2/neu-transformed cells. Thus, targeting these altered metabolic pathways might represent an attractive therapeutic approach at least for the treatment of patients with HER-2/neu overexpressing tumors.
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