Approximately 70 percent of human cancers show a similar metabolic phenotype, such as aerobic glycolysis characterized by increased glucose uptake and enhanced lactate production. In addition, human cancers are often characterized by dysregulated signal transduction due to imbalances in post-translational modifications (PTMs) of proteins. This suggests the interplay of signal transduction and metabolic pathway networks.
Dr. Taro Hitosugi, Ph.D., employs phosphoproteomics and metabolomiscs approaches to studying molecular mechanisms of this interplay. The ultimate goal of his research is to help patients through discoveries of metabolic enzymes or metabolites that are important for tumorigenesis with the hope of translating this work from bench to the bedside.
- Understanding how pyruvate metabolism is determined by tyrosine phosphorylation of pyruvate kinase M2 (PKM2) in human cancers. Previous studies by Dr. Hitosugi show that PKM2 is commonly tyrosine phosphorylated and inhibited in cancer cell lines. He is employing a combined approach, including proteomics and RNA-mediated interference screening studies to address the question of how downregulated PKM2 activity increases lactate production, while being just one step downstream from PKM2.
- Deciphering the role of mitochondria localized oncogenic tyrosine kinases in cancer metabolism. Previous studies by Dr. Hitosugi show that oncogenic tyrosine kinases (OTKs) can localize into the mitochondria, leading to the hypothesis that OTKs may phosphorylate metabolic enzymes to regulate mitochondrial metabolic pathways. He is studying the approaches of phosphoproteomics and metabolomics using subfractionation of mitochondria lysates to identify critical mitochondrial metabolic pathways for OTK-positive cancers.
- Exploring how PTMs other than tyrosine phosphorylation regulate cancer metabolism. This research builds on exploring how other PTMs, such as cysteine oxidation, lysine ubiquitination and glycosylation affect cancer metabolism. These PTMs are important because they are connectors that link reactive oxygen species, ubiquitin ligase and glycosyltransferase signaling pathways with metabolic pathways.
Significance to patient care
Dr. Hitosugi believes that the overall understanding of the interplay between signal transduction and cancer metabolism will help design novel drugs that specifically target the intersection between the dysregulated signaling and the changes in metabolisms that occur during transformation. In addition, this knowledge will help develop novel strategies for the combined use of kinase inhibitors and metabolic enzyme inhibitors. Also, his lab is pursuing discoveries in tumor suppressive metabolites in normal cells that can be used directly for the development of anti-cancer drugs with minimal side effects due to the chemical compounds in such metabolites already being present in normal cells.
- American Society of Hematology (ASH) Scholar Award, 2010