Abstract
Tumor cells reprogram their metabolic pathway to meet their energetic needs during tumor progression. Highly proliferating or transformed cells are able to switch their metabolism from oxidative phosphorylation-based energy production to aerobic glycolysis. This switch called Warburg effect is recognized as a bioenergetic signature of cancer cells.
The PI3K pathway is one of the most commonly altered signaling in human cancers and plays a primary role in the establishment of the Warburg effect by inducing the transcriptional activation of glycolytic genes, increasing the surface expression of glucose transporters, stimulating lipid synthesis.
Using a novel, clinically relevant, mouse model in which thyrocyte-specific deletion of Pten constitutively activates the PI3K signaling cascade, we have identified a previously unrecognized in vivo mechanism through which PI3K activation subverts energy metabolism in thyroid cells by repressing oxidative phosphorylation well before full neoplastic transformation takes place, leading to the coordinated downregulation of the expression of genes encoding for members of both the TCA cycle and oxidative phosphorylation pathways.
We have now extended our analysis to mice carrying the cancer-associated, constitutively active Pik3caH1047R allele, and have observed the same downregulation of TCA and oxidative phosphorylation genes in the thyroid of Pik3caH1047R heterozygous mice, suggesting that the phenotype observed in the Ptenthyr-/− mice is solely due to the activation of the PI3K pathway.
Lactate dehydrogenase is a tetrameric enzyme comprising two major subunits, A and/or B, and catalyzes the forward and backward conversion of pyruvate to lactate.
Previous data from our lab showed an increase of lactate levels in thyroids from both young, tumor-free and older Ptenthyr-/− mice, indicating an increase in glycolysis metabolic flux even before full transformation.
To test the therapeutic value of Lactate dehydrogenase inhibition both in tumor initiation and in tumor maintenance, we have undertaken a combined pharmacological and genetic approach.
Interestingly, our data suggest that pharmaceutical and genetic LDHA inhibition results in a significant reduction in the proliferation rate of different thyroid cancer cell lines.
Moreover, to test the hypothesis that the glycolytic switch is necessary for full neoplastic transformation of Pten−/− thyroids and to prove that the LDHA enzyme plays a crucial rule in this process, we have generated a new (Pten,Ldha)thyr-/− mouse model that is being currently phenotypically and molecularly characterized to assess the effect of Ldha deficiency on thyroid hyperplasia, proliferation index, lactate content, and TCA cycle/OXPHOS gene expression.
Taken together, these data pave the way to the full understanding of the metabolic landscape induced by the activation of the PI3K pathway, and to the possibility of exploring therapeutic approaches targeting metabolic deregulation in vivo.
Citation Format: Daniela De Martino, Antonio Di Cristofano. PI3K-directed metabolic reprogramming in thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 54.
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