Evaluation of efficacy for targeting enzymes of mitochondrial one-carbon metabolism for cancer treatment.

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15021
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kanazawa University
• Principal Investigator: Nishimura Tatsunori 金沢大学, がん進展制御研究所, 助教 (10624869)
• Research Collaborator: Nakata Asuka ; Chen Xiaoxi ; Nishi Kurumi ; Meguro Makiko (Horike Makiko) ; Sasaki Soichiro ; Kita Kenji ; Horike Shin-ichi ; Saito Kaori ; Kato Keiko ; Igarashi Kaori ; Murayama Takahiko ; Kohno Susumu ; Takahashi Chiaki ; Mukaida Naofumi ; Yano Seiji ; Soga Tomoyoshi ; Tojo Arinobu ; Gotoh Noriko
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 葉酸代謝酵素 / ミトコンドリア / 腫瘍原生能

Outline of Final Research Achievements

In this study, we evaluated whether enzymes of mitochondrial One-carbon metabolism can be a novel drug target to cure cancer patients. Among the enzymes, we focused especially on MTHFD1L and MTHFD2, which were not studied in detail yet. As a result, when we knock-downed either genes of cancer cells with shRNA, not only their cellular proliferation was inhibited, but also their tumor initiating ability was also inhibited. The reason for the former phenotype was the inhibition of de novo synthesis of purine nucleotides, and that for the later one was the accumulation of AICAR, which is one of the intermediates during the purine nucleotides synthesis, triggered by the down-regulation of either MTHFD1L or MTHFD2.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究ではMTHFD1LとMTHFD2を阻害することができれば、腫瘍の増大の阻止に加え、再発や転移を抑制できることが示唆された。このことからMTHFD1LとMTHFD2の阻害剤が開発されれば、新規の抗癌剤になりうる可能性が高いことが示唆された。
葉酸代謝酵素は古くから抗癌剤のターゲットとされてきたが、副作用が強い等の理由から使用できる範囲が限られていた。しかし、我々が本研究で着目したミトコンドリア内葉酸代謝酵素、MTHFD1LとMTHFD2は成体の正常細胞では発現が低いため、これらの酵素を標的とした場合、より副作用が少ないことが期待される。