Cancer treatments targeting mitochondrial enzymes involved in one-carbon metabolism

DOI Open Access
  • Nishimura Tatsunori
    Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University
  • Jin Lee
    Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University
  • Xiaoxi Chen
    Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University
  • Tojo Arinobu
    Division of Molecular Therapy, The Institute of Medical Science, The University of Tokyo
  • Gotoh Noriko
    Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University

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  • ミトコンドリア内葉酸代謝酵素を標的としたがん治療

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Abstract

<p>One-carbon metabolism, also called folate-mediated metabolism, has been targeted for the treatment of patients with cancer. However, therapeutic windows available to the inhibitors of one-carbon metabolism are limited and some patients have been shown to develop resistance to anti-folate drugs. Recently, we showed that mitochondrial enzymes involved in one-carbon metabolism have greater specifi city toward cancer cells than the cytoplasmic enzymes. In our study, we knocked down the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase (MTHFD2) gene in order to inhibit the activity of one such mitochondrial enzyme. Cell cycle progression was analyzed using propidium iodide, and stem cell-like nature was evaluated in terms of aldehyde dehydrogenase activity on a fl ow cytometric setup. Our results showed a drastic decrease in cellular proliferation and stem cell-like phenotypes in the MTHFD2 knockdown cells. From a mechanistic point of view, the inhibition of cellular growth could be predominantly ascribed to the depletion of purine nucleotides, and that of stem cell-like phenotypes was attributable to the accumulation of 1-(5'-phosphoribosyl)-5-amino-4- imidazolecarboxamide.</p>

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