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.
Highlights
The 43 kDa cyclic AMP-responsive element binding protein (CREB) is a member of the large family of basic leucine zipper-containing transcription factors (TF) and plays a key role in many physiologic as well as pathophysiologic processes including cell growth, differentiation, apoptosis, cell cycle progression and immune response amongst others [1]
We show here that altered cAMPresponsive element binding protein (CREB) expression levels and function are associated with changes in the cellular metabolism
Overall 23 differentially expressed protein spots have been identified from three biological replicates, from which 13 proteins were down-regulated including four different forms of alpha-tubulin and 10 upregulated upon CREB down-regulation
Summary
The 43 kDa cyclic AMP (cAMP)-responsive element binding protein (CREB) is a member of the large family of basic leucine zipper (bZIP)-containing transcription factors (TF) and plays a key role in many physiologic as well as pathophysiologic processes including cell growth, differentiation, apoptosis, cell cycle progression and immune response amongst others [1]. The CREB/CBP complex induces a transcriptional machinery leading to activation of cAMP-responsive element (CRE) containing gene promoters. CREB mediates transcriptional responses to different stimuli including hormones, growth factors and neurotransmitters thereby acting as mediator between signaling pathways and their downstream activation target [3, 6]. Based on its frequent overexpression and persistent activation CREB is involved in the malignant transformation process [7]. This is mediated by aberrant activation of cAMP signal transductiondependent pathways such as G-coupled receptors, receptor tyrosine kinase (RTK) like human epidermal growth factor receptor 2 (HER-2/neu) and the cytokine/ JAK/STAT signaling cascades, as well as signaling events downstream of CREB
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