Annual Report 2024
Team Makinoshima
Hideki Makinoshima, Sho Tabata
Introduction
It is believed that the breakdown of homeostasis, which maintains a constant state in the body, is the cause of carcinogenesis and its progression. We are continuing our research based on the hypothesis that when the limits of homeostasis is exceeded, carcinogenesis-inducing metabolites and metabolic systems specific to cancer cells are overproduced or reduced within the individual, and that the metabolites themselves contribute to the development and malignancy of cancer. Through these studies, we aim to elucidate the true nature of cancer from the perspective of metabolism.
The Team and What We Do
In fiscal 2024, we continued our efforts to identify metabolites and metabolic pathways specific to cancer and develop new drugs that target them. In a joint research project between the Keio University Institute for Advanced Life Sciences and the National Cancer Center, we collected samples from patients, cancer cell lines, cancer stromal cells, and mouse models, and performed metabolomic analysis on cancer. Through joint research with the National Cancer Center Research Institute, the National Cancer Center Hospital East, and the Yamagata University Faculty of Medicine, we constructed metabolite profiles from clinical samples through metabolomic analysis. Furthermore, through collaborative and contract research partnerships with companies, we conducted research based on metabolome analysis with Ajinomoto Co., Inc., Otsuka Pharmaceutical Co., Ltd., JA Kushibiki Noko Ren, and Midori Service.
In drug discovery research targeting metabolic pathways characteristic of cancer, we are studying the regulatory mechanisms of nucleic acid biosynthesis pathways. Maintaining an appropriate concentration balance of purine bases (A, G) and pyrimidine bases (C, T/U), required for nucleic acid synthesis, is essential for the fidelity of DNA replication and RNA transcription, and an imbalance of these bases is known to promote genome instability and increase mutation rates. However, the detailed mechanism by which cells control the supply balance between purines and pyrimidines remains unclear. In this study, we analyzed the dynamics of the purine and pyrimidine metabolic pathways and the mechanism of balance regulation using cultured mammalian cells. Elucidating the molecular basis of base balance control in nucleic acid metabolism will provide clues for a deeper understanding of metabolic abnormalities and drug sensitivity in cancer cells.
Research Activities
We aimed to elucidate the regulatory mechanisms of the de novo biosynthetic and salvage pathways of nucleic acid metabolism, including purine and pyrimidine nucleotides, which are the raw materials for DNA and RNA synthesis. We conducted research on nucleic acid metabolism in cancer, focusing on allosteric control mechanisms and feedback mechanisms, which are important in metabolic research. Two metabolic pathways are known for the biosynthesis of purine nucleotides: the de novo synthesis pathway and the salvage pathway. Historically, anticancer drug development has focused on de novo biosynthetic pathways related to folate metabolism. Using small cell lung cancer cell lines, we have demonstrated that cancer cells preferentially utilize the salvage pathway. Antifolates inhibit purine biosynthesis by inhibiting the de novo synthesis pathway, but we have continued to study the drug resistance mechanism by which the effectiveness of the drug decreases during treatment due to the presence of the salvage pathway. Furthermore, this year we have advanced research into the metabolic control mechanisms of pyrimidine bases, in addition to purine base metabolism.
Education
We educated and trained researchers, research assistants, and students at Keio University.
Hideto Ohta (Research Assistant, Shonai Regional Industry Promotion Center)
Miyu Narita (Research Assistant, Shonai Regional Industry Promotion Center)
Shin Goto (Special research student, Keio University Institute for Advanced Biosciences)
Future Prospects
From next fiscal year onwards, the group will continue to identify the control mechanisms of nucleic acid metabolism specific to cancer and new nucleic acid metabolic pathways, and aim to develop new treatments that target these. Furthermore, the group aims to promote collaborative research with companies and acquire new research funds.