Selective effects of metformin on the cells with PIK3CA activating mutations

Research Project

Project/Area Number	18K06696
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 47040:Pharmacology-related
Research Institution	Institute for Developmental Research Aichi Developmental Disability Center
Principal Investigator	Suzuki Yasuyo 愛知県医療療育総合センター発達障害研究所, 遺伝子医療研究部, 主任研究員 (60416188)
Project Period (FY)	2018-04-01 – 2023-03-31
Project Status	Completed (Fiscal Year 2022)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords	過成長症候群 / PROS / PIK3CA / メトホルミン / 体細胞モザイク変異 / 体細胞モザイク変 / PI3K / ＰＩ３Ｋ / ｍＴＯＲ / ＰＲＯＳ
Outline of Final Research Achievements	Recently, mosaic or segmental overgrowth, a clinical condition caused by heterozygous somatic activating mutations in PIK3CA, was established as PIK3CA-related overgrowth spectrum (PROS). PROS is caused by activating mutations in PIK3CA encoding the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, also known as p100α). We have shown that metformin selectively inhibits the proliferation of fibroblasts from PROS patients, but not healthy fibroblasts. Since PROS is a developmental disorder in children, metformin is a candidate drug for treating PROS. However, the mechanism that metformin selectively inhibits cell proliferation of PROS cells is unclear. In this study, to determine the effect of metformin on cells with activating mutations in PIK3CA, biochemical and molecular biological analyses were performed using human breast cancer MDA-MB-453 cells with the heterozygous PIK3CA mutation (c.3140A>G).
Academic Significance and Societal Importance of the Research Achievements	本研究は、我々が発見した「PIK3CAの活性化変異を有する細胞の増殖を選択的に抑制するメトホルミンの作用」という、これまでにない新しい観点から行った研究である。細胞内のシグナル伝達や代謝に及ぼすメトホルミンの作用には、未だ不明な点が多い。本研究により、メトホルミンの新たな作用機序を明らかにすることは、PROSの病態に関する新たな知見が得られるだけでなく、治療につながる可能性が高い。