Abstract 52: NF-kB promotes a Warburg metabolic profile in pediatric sarcomas

In contrast to normal cells that use mitochondrial oxidative phosphorylation for ATP production in aerobic conditions, many cancer cells depend on glycolysis even in the presence of sufficient oxygen. This process is known as aerobic glycolysis or the Warburg effect. Recent reports have shown that both the classical and alternative signaling pathways of NF-κB play important roles in controlling the metabolic profile of cancer and normal cells, respectively. However, how these signaling pathways affect the metabolism of pediatric sarcomas has not yet been explored. Here, we show NF-κB activity undergoes a shift in signaling from an alternative to a classical pathway in the genesis of sarcoma subtypes, rhabdomyosarcoma and osteosarcoma. Inhibition of classical NF-κB in sarcoma cells restores alternative signaling, as well as an oxidative metabolic phenotype in vitro and in vivo. In contrast, forced expression of the alternative pathway in rhabdomyosarcoma or in osteosarcoma cells is unable to reverse NF-κB classical activity, suggesting that the activation of the classical pathway in sarcomagenesis dominates over alternative signaling. Furthermore, we observed that inhibition of NF-κB in sarcoma cells reduced the expression of the glycolytic gene, hexokinase 2 (HK2). Through chromatin immunoprecipitation (ChIP) assays, we show that HK2 is a direct NF-κB target. Moreover, deletion of HK2 by using shRNA shifts the metabolic profile in sarcoma cells away from a warburg effect. These findings demonstrate a crucial role for classical NF-κB in sarcomagenesis and suggest that NF-κB metabolically reprograms sarcoma cells by regulating HK2. Citation Format: Yuichi Ijiri, Priya Londhe, Cheryl London, Peter J. Houghton, Denis C. Guttridge. NF-kB promotes a Warburg metabolic profile in pediatric sarcomas. [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 52.