p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation.
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.
Kawauchi
Keiko
K
Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, Kosugi-cho 1-396, Nakahara-ku, Kawasaki-shi, Kanagawa 211-8533, Japan.
Araki
Keigo
K
Tobiume
Kei
K
Tanaka
Nobuyuki
N
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D011905:Genes, ras; D005947:Glucose / Q000378:metabolism*; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D051274:Glucose Transporter Type 3; C498144:Rela protein, mouse; C495689:Slc2a3 protein, mouse; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D019344:Lactic Acid; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D018631:ras Proteins; D005947:Glucose