Research Paper Volume 2, Issue 11 pp 823—842

Figure 8. STAT3 acts as a central mediator of cell metabolism through both HIF-1α-dependent and -independent mechanisms. Many oncogenic signals can trigger the constitutive activation of STAT3, either directly or indirectly. Activated STAT3 migrates into the nucleus, where it up-regulates HIF-1α expression and lowers the expression of mitochondrial mRNAs, either via direct or indirect mechanisms. HIF-1α induces the transcription of different genes involved in glycolysis; the glucose channel GLUT-1 enhances glucose intake; the kinase PDK-1 reduces the conversion of pyruvate into Acetyl-CoA, favouring its catabolism into lactate; other enzymes, such as ENO-1 or PFK-L, sustain glycolysis by improving glucose metabolism. Increased glycolysis results in enhanced lactate production, and allows the cell to maintain a high ATP/ADP ratio even in the presence of reduced mitochondrial respiration. All together, this results in enhanced proliferative potential. The decreased mitochondrial activity, insensitive to HIF-1α silencing, is instead predominantly caused by the down-regulation of nuclear-encoded mitochondrial genes and leads to reduced oxidative metabolism, which in turn prevents ROS over-production protecting the cell from senescence and apoptosis. The metabolic switch from oxidative phosphorylation to aerobic glycolysis, typical of most cancer cells, makes cells highly sensitive to glucose deprivation.