Linking CREB function with altered metabolism in murine fibroblast-based model cell lines

• Published in: Oncotarget Vol. 8; no. 57; pp. 97439 - 97463
• Main Authors: Steven, André, Leisz, Sandra, Wickenhauser, Claudia, Schulz, Kristin, Mougiakakos, Dimitrios, Kiessling, Rolf, Denkert, Carsten, Seliger, Barbara
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 14.11.2017
• Subjects: Medicin och hälsovetenskap; Research Paper; HER-2/neu; metabolism; CREB; mitochondria; ROS
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.22135

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.