Abstract 1261: A preneoplastic switch to glycolytic metabolism driven by a PI3K-induced transcriptional program

Abstract Most cancer cells exhibit a peculiar metabolic behavior, producing energy by aerobic glycolysis instead of oxidative phosphorylation (Warburg effect). Several oncogenes directly drive this switch modulating the levels and activity of, among others, Hexokinase II, Lactate Dehydrogenase A, Pyruvate Kinase M2, and Pyruvate Dehydrogenase Kinase 1. We have generated a Pten-/- mouse model in which the PI3K pathway is selectively activated in the thyroid epithelial cells, leading to hyperplasia which later progresses to follicular carcinoma. Using proteomics to identify proteins differentially expressed in early hyperplastic lesions, we have found that the levels of many tricarboxylic acid cycle proteins are down-regulated in mutant thyroids. Down-regulation of these proteins is due to reduced mRNA expression, and results in reduced oxidative phosphorylation and enhanced glycolysis (over 3-fold increase in lactate production in mutants vs. wt). Furthermore, although mutant thyroids cells have a normal number of mitochondria, the expression of most mitochondrially-encoded genes is heavily down-regulated. Strikingly, none of the genes and proteins classically associated with the Warburg effect is found deregulated in the mutant thyroid cells. Analysis of the expression of transcription factors and co-activators involved in cellular metabolism revealed that the decrease in TCA cycle and OXPHOS genes is due to a reduction in ERRα, ERRγ, PPARα and PPARγ levels. Conversely, none of the co-activators analyzed (PRC1, PGC-1α, and PGC-1β) exhibited changes in mRNA expression. Pharmacological and genetic PI3K inhibition in mouse tumor-derived thyroid cancer cell lines increased the expression levels of both TCA cycle OXPHOS genes. Moreover, it also increased mtDNA amount, suggesting that the transition from hyperplasia to cancer involves additional alterations of the metabolic machinery. Likewise, PI3K inhibition induced a marked decrease in lactate secretion. Finally, these thyroid cancer cell lines exhibited high sensitivity to glycolysis inhibitors such as 3-bromopyruvate. Based on these compelling data, we propose a novel mechanism leading to the Warburg effect in preneoplastic lesions: PI3K activation initiates a coordinated rearrangement of the expression of metabolic genes, which favors aerobic glycolysis at the expense of TCA/OXPHOS. The elucidation of this process will lead to innovative targeted approaches to selectively disrupt tumor progression, while preserving normal metabolism in non mutated cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1261. doi:10.1158/1538-7445.AM2011-1261