UCP2 overexpression enhanced glycolysis via activation of PFKFB2 during skin cell transformation
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Annapoorna Sreedhar1, Petra Petruska1, Sumitra Miriyala2, Manikandan Panchatcharam2 and Yunfeng Zhao1
1Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
2Department of Anatomy and Cell Biology, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
Yunfeng Zhao, email: firstname.lastname@example.org
Keywords: mitochondrial uncoupling 2; PFKFB2; mitochondria; glycolysis; skin cells
Received: June 24, 2017 Accepted: August 03, 2017 Published: September 08, 2017
Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane transporter which is often upregulated in human cancers. However, how this anion transporter affects tumorigenesis is not well understood. Using the skin cell transformation JB6 model, we demonstrated that UCP2 overexpression activated phosphofructokinase 2/fructose-2,6-bisphosphatase 2 (PFKFB2), a key regulator of glycolysis. In conjunction, upregulation of PFKFB2 expression correlated with elevated fructose 2,6-bisphosphate (Fru-2,6-P2) levels, 6-phosphofructo-1-kinase (PFK-1) activity, glucose uptake, and lactate production. Inhibiting PFKFB2 expression suppressed UCP2-mediated skin cell transformation, decreased cell proliferation, and enhanced mitochondrial respiration, while dampening aerobic glycolysis. The AKT signaling pathway was activated in the UCP2 overexpressed cells; furthermore, the activated AKT signaling contributed to the activation of PFKFB2. Whereas AKT inactivation blocked PFKFB2 activation, suggesting that AKT activation is an important step in PFKFB2 activation. Collectively, our data suggest that UCP2 is a critical regulator of cellular metabolism during cell transformation. Our data also demonstrate a potentially novel mechanism to understand UCP2’s tumor-promoting role, which is through the AKT-dependent activation of PFKFB2 and thereby, the metabolic shift to glycolysis (the Warburg effect).
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