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

Steven A, Leisz S, Wickenhauser C, Schulz K, Mougiakakos D, Kiessling R, Denkert C, Seliger B (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Oncotarget Impact Journals

Book Volume: 8

Pages Range: 97439-97463

Journal Issue: 57

DOI: 10.18632/oncotarget.22135

Abstract

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.

Authors with CRIS profile

Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie

Involved external institutions

Karolinska Institute SE Sweden (SE) Martin-Luther-Universität Halle-Wittenberg (MLU) DE Germany (DE) Deutsches Zentrum für Diabetesforschung e.V. (DZD) DE Germany (DE)

How to cite

APA:

Steven, A., Leisz, S., Wickenhauser, C., Schulz, K., Mougiakakos, D., Kiessling, R.,... Seliger, B. (2017). Linking CREB function with altered metabolism in murine fibroblast-based model cell lines. Oncotarget, 8(57), 97439-97463. https://doi.org/10.18632/oncotarget.22135

MLA:

Steven, André, et al. "Linking CREB function with altered metabolism in murine fibroblast-based model cell lines." Oncotarget 8.57 (2017): 97439-97463.

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