Abstract 445: Efficient tumorigenesis after genetic dissociation of glycolysis and the TCA cycle

Abstract

Abstract Virtually all tumors undergo some form of metabolic re-programming to match anabolic needs with energy supply. The best-known form of this is the Warburg effect by which tumors become more reliant on glycolysis over mitochondrial oxidative phosphorylation, even when their oxygen supply is abundant. Nonetheless, mitochondria retain some residual activity in order to provide both ATP and critical metabolic building blocks and other substrates for processes such as lipid biosynthesis and protein acetylation. The pyruvate dehydrogenase (PDH) complex (PDC) is the main enzymatic link between glycolysis and the TCA cycle and irreversibly converts the end-stage glycolytic product pyruvate into the critical TCA substrate, acetyl-coenzyme A (AcCoA). In a mouse model of the pediatric liver cancer hepatoblastoma (HB), we recently showed PDH to be highly up-regulated, despite reduced mitochondrial function. We postulated that this might represent a response to pyruvate depletion due to upstream shunting of glycolytic intermediates into anabolic pathways. To test this idea, we examined in vivo tumorigenesis in mice bearing a hepatocyte-specific conditional knockout of the pdha1 subunit (KO mice). The survival of these mice was marginally longer than the wild-type (WT) controls, although tumor sizes at time of death were ~20% smaller. KO mice expressed virtually no PDH (and hence no PDC activity) and had high blood lactate levels. This suggested that they succumbed with smaller tumors as a result of severe lactic acidosis that could not be corrected by hyperventilation due to respiratory compromise by the large HBs that restricted lung volumes. This was supported by studies performed in a modified form of this model in which only tumors were PDC deficient whereas the surrounding liver parenchyma was not. These mice now survived longer than did their WT counterparts and their tumors reached comparable sizes. They also had lower lactate levels than the pan-KO mice. Oxygen consumption rates of WT and KO tumors were similar yet were lower than those of normal livers. Rates of fatty acid β-oxidation by WT and KO tumors were also lower than those of liver, indicating that both types of tumors preferentially divert fatty acids into membrane synthesis rather than toward supplying AcCoA. Taken together, these findings demonstrate the remarkable capacity for nearly normal HB pathogenesis despite the severing of glycolysis from the TCA cycle. Citation Format: Laura E. Jackson, Sucheta Kulkarni, Huabo Wang, Jie Lu, Sivakama Bharathi, Radha Uppala, Mulchand S. Patel, Eric S. Goetzman, Edward V. Prochownik. Efficient tumorigenesis after genetic dissociation of glycolysis and the TCA cycle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 445. doi:10.1158/1538-7445.AM2017-445