Abstract
One of the fundamental problems in animal cells is the coordination of the metabolic program with cell proliferation-associated bioenergetic demand. Primary T lymphocytes rapidly switch from a quiescent phase to a rapid-proliferation phase one day after antigen stimulation. To meet the bioenergetic and biosynthetic demand for this burst of proliferation, T cells rapidly reprogram their metabolic pathways from fatty acid beta-oxidation and glucose aerobic respiration to glycolysis (converting glucose to lactate) and glutaminolysis (converting glutamine to metabolites of the TCA cycle). This is reminiscent of tumor-associated metabolic reprogramming in many ways. Recent work has indicated that oncogenic signaling can reform tumor metabolic programs by targeting relatively few key metabolic genes. However, we found that global regulation of the metabolic gene transcriptome precedes the switch of T cell metabolic activities. In silico analysis of DNA-binding motifs associated with the metabolic gene expression profile revealed HIF1a, c-Myc and p53 as three of the top-ranked candidate transcription factors responsible for T cell metabolic reprogramming. Consistent with this, HIF1a, c-Myc and p53 are each highly induced in primary T cells upon antigen stimulation and have been implicated in the regulation of tumor metabolism. However, while germline deletion of p53 and acute deletion of HIF1a showed no defects in metabolic reprogramming upon antigen stimulation, acute deletion of c-Myc in mature T lymphocytes profoundly reduced antigen-stimulated glycolysis and glutamine oxidation in primary T cells. In addition, c-Myc deletion significantly compromised T cell growth and T cell proliferation after antigen stimulation. Finally, we found that many of the key metabolic genes involved in glycolysis and glutamine oxidation are regulated in a c-Myc-dependent manner. Our results further suggest a novel c-Myc dependent metabolic pathway linking glutamine oxidation to the biosynthesis of polyamines, which is a group of metabolites essential for cell proliferation. Our studies clearly demonstrate that primary T lymphocytes drive a c-Myc-dependent metabolic reprogramming upon antigen stimulation, which may represent a general mechanism of the metabolic reprogramming under both pathological and physiological conditions.
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 2801. doi:10.1158/1538-7445.AM2011-2801