Major Research Area
Ever since the great success of gleevec in cancer biology, tremendous efforts have made to identify new effective cancer targets. However, the targets that delivered FDA-approved drugs are limites and extremely biased in the mediators of signal pathways such as kinases etc. However, in many times, those targets show slim efficacy with rapid occurrence of resistance. For this reason, it is necessary to explore the targets that can tolerate heterogeneity of cancers with sufficient efficacy. Although the targets in cancer-specific metabolism are emerging as alternative targets, they mainly focus on energy metabolism involving glucose or fatty acids. We are addressing potentials of amino acid metabolism or amino acid signaling as cancer targets Work is in progress in the following areas.
-
Investigating the role of amino acids on cellular physiologies such as cell growth and death, autophagy, and circadian rhythm.
-
Investigating the mechanism of amino acid signaling
-
Identification of intracellular amino acid sensors
-
Investigating the molecular network between translation, metabolism, and cancer
-
Identification of novel druggable targets
Aminoacyl-tRNA synthetases and Diseases
Translation is dynamically controlled by intracellular amino acid and ATP energy availabilities. Especially, intracellular amino acid availability is determined by amino acid consumption (aminoacyl-tRNA synthesis and protein synthesis) and supply (extracellular uptake, metabolic synthesis, or protein turnover). Thus, intracellular amino acid sensing is closely related to the regulation of translation and other cellular physiologies. Aminoacyl-tRNA synthetases (ARSs) catalyze the first step reaction in protein synthesis to ligate each amino acid into its cognate tRNAs. ARSs are very unique enzymes that recognize very important molecules, amino acids, tRNA, and ATP. Through this catalytic property, ARSs can have diverse regulatory functions in translation and other biological processes. Indeed, leucyl-tRNA synthetase (LRS) is the first intracellular leucine sensor for coordinating mTORC1 signaling pathway, autophagy, and translation. Our research aims to reveal the amino acid sensing functions of ARSs in diverse cellular physiologies and how these pathways are linked to human diseases.
Metabolic differences between Normal and Cancer cells
Cancer cells preferentially utilize glycolysis over oxidative phosphorylation for cell growth, even in the presence of normal oxygen levels, a phenomenon known as the “Warburg effect”. In normal cells, glucose is metabolized to pyruvate, which is completely oxidized to CO2 through the TCA cycle and the oxidative phosphorylation (OXPHOS) in the mitochondria. However, cancer cells generate lactate using glucose regardless of the availability of O2 (aerobic glycolysis). This glucose utilization generates metabolic intermediates such as glucose-6-phosphoate, which is used for carbon backbone of nucleic acids and amino acids. Instead, glutamate produced during glutaminolysis serves as the major substrate to generate ATP energy and intermediate acetyl-CoA is used for lipid production. The increased synthesis of nucleic acid, amino acids, and lipids promote cancer cell growth
Regulation of mTORC1 pathway by Leucine
Amino acids are required for the activation of the mammalian target of rapamycin (mTOR) kinase which is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulate protein translation, cell size, cell growth, and autophagy. Ras-like Rag GTPases are shown to be amino acid-specific regulators of the mTORC1 pathway. Among amino acids, intracellular leucine is recognized as a major signal nutrient that regulates mTORC1. Leucyl-tRNA synthetase (LRS) is an mTORC1-associated protein and plays an essential role for leucine-induced mTORC1 activation. Among the components of mTORC1, LRS directly interacts with RagD GTPase in leucine-dependent manner and functions as a GTPase activating protein (GAP) for RagD GTPase to activate mTORC1