Nutrient deprivation induces the Warburg effect through ROS/AMPK-dependent activation of pyruvate dehydrogenase kinase
Journal
Biochimica et Biophysica Acta - Molecular Cell Research
Journal Volume
1833
Journal Issue
5
Pages
1147-1156
Date Issued
2013
Author(s)
Abstract
The Warburg effect is known to be crucial for cancer cells to acquire energy. Nutrient deficiencies are an important phenomenon in solid tumors, but the effect on cancer cell metabolism is not yet clear. In this study, we demonstrate that starvation of HeLa cells by incubation with Hank's buffered salt solution (HBSS) induced cell apoptosis, which was accompanied by the induction of reactive oxygen species (ROS) production and AMP-activated protein kinase (AMPK) phosphorylation. Notably, HBSS starvation increased lactate production, cytoplasmic pyruvate content and decreased oxygen consumption, but failed to change the lactate dehydrogenase (LDH) activity or the glucose uptake. We found that HBSS starvation rapidly induced pyruvate dehydrogenase kinase (PDK) activation and pyruvate dehydrogenase (PDH) phosphorylation, both of which were inhibited by compound C (an AMPK inhibitor), NAC (a ROS scavenger), and the dominant negative mutant of AMPK. Our data further revealed the involvement of ROS production in AMPK activation. Moreover, DCA (a PDK inhibitor), NAC, and compound C all significantly decreased HBSS starvation-induced lactate production accompanied by enhancement of HBSS starvation-induced cell apoptosis. Not only in HeLa cells, HBSS-induced lactate production and PDH phosphorylation were also observed in CL1.5, A431 and human umbilical vein endothelial cells. Taken together, we for the first time demonstrated that a low-nutrient condition drives cancer cells to utilize glycolysis to produce ATP, and this increases the Warburg effect through a novel mechanism involving ROS/AMPK-dependent activation of PDK. Such an event contributes to protecting cells from apoptosis upon nutrient deprivation. ? 2013 Elsevier B.V.
SDGs
Other Subjects
glucose; lactate dehydrogenase; lactic acid; mitogen activated protein kinase; mitogen activated protein kinase inhibitor; pyruvate dehydrogenase kinase; reactive oxygen metabolite; apoptosis; article; cancer cell; cell viability; controlled study; enzyme activity; glucose transport; glycolysis; HeLa cell; human; human cell; nutritional deficiency; oxygen consumption; priority journal; protein phosphorylation; signal transduction; umbilical vein endothelial cell; Adenosine Triphosphate; AMP-Activated Protein Kinases; Apoptosis; Energy Metabolism; Food Deprivation; Glycolysis; HeLa Cells; Humans; Isotonic Solutions; Lactic Acid; Mutation; Neoplasms; Phosphorylation; Protein-Serine-Threonine Kinases; Pyruvic Acid; Reactive Oxygen Species; Transcriptional Activation
Type
journal article