p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation

Abstract

Cancer cells use aerobic glycolysis preferentially for energy provision and this metabolic change is important for tumour growth. Here, we have found a link between the tumour suppressor p53, the transcription factor NF-kappaB and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKKalpha and IKKbeta and subsequent NF-kappaB activity were enhanced. Activation of NF-kappaB, by loss of p53, caused an increase in the rate of aerobic glycolysis and upregulation of Glut3. Oncogenic Ras-induced cell transformation and acceleration of aerobic glycolysis in p53-deficient cells were suppressed in the absence of p65/NF-kappaB expression, and were restored by GLUT3 expression. It was also shown that a glycolytic inhibitor diminished the enhanced IKK activity in p53-deficient cells. Moreover, in Ras-expressing p53-deficient cells, IKK activity was suppressed by p65 deficiency and restored by GLUT3 expression. Taken together, these data indicate that p53 restricts activation of the IKK-NF-kappaB pathway through suppression of glycolysis. These results suggest that a positive-feedback loop exists, whereby glycolysis drives IKK-NF-kappaB activation, and that hyperactivation of this loop by loss of p53 is important in oncogene-induced cell transformation.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…In addition to the established role of p53 in cell cycle arrest and apoptosis, recent evidence has demonstrated that p53 reduces glycolytic flux and increases oxidative phosphorylation, halting the Warburg effect. [137][138][139][140][141][142][143] TIGAR (Tp53-induced glycolysis and apoptosis regulator) was identified to function as a fructose-2,6-bisphosphatase (Fru-2,6-BP), antagonizing the third step of glycolysis and thereby redirecting metabolite flux to the pentose phosphate pathway. [138][139][140] Interestingly, basal or low levels of p53 expression have been suggested to provide antioxidant effects and thus elicit cellular protection rather than cell death.…”

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer

“…Glucose consumption and lactate production in CRC cells were analyzed as previously described (16). Glucose and lactate levels in the culture medium were also determined by using the glucose assay kit and lactate assay kit, respectively.…”

Uncovering metabolism in rhabdomyosarcoma

“…81,82 Loss of p53 activity Different regulators in healthy tissues control the glucose metabolism, including p53, AKT, Myc and HIF proteins. P53, in particular, inhibits the expression of glucose transporters (GLUTs), such as GLUT1 and GLUT4 83 or GLUT3, 84 and reduces glucose utilization in the glycolytic pathway [85][86][87] (Fig. 3).…”