Anti-aging drugs by targeting PTEN

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K20661
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Studies on the Super-Aging Society
• Research Institution: Kobe University
• Principal Investigator: Suzuki Akira 神戸大学, 医学研究科, 教授 (10311565)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Keywords: PTEN / 長寿薬 / がん抑制遺伝子

Outline of Final Research Achievements

Two E3 SUMOylating enzymes (X, Y) and the deubiquitinating enzyme Z were identified as PTEN binding and destabilising molecules. Knockdown of X and Y increased PTEN, decreased phosphorylated AKT and reduced cell proliferation, whereas knockdown of Z resulted in nuclear localisation of PTEN and increased PTEN protein. X and Y homozygous deletion mice have been generated and their longevity is currently being investigated.
On the other hand, we found that WWP2, one of the 5 PTEN E3 ligases, has the highest PTEN destabilising effect, so a PTEN-WWP2 binding visualisation system was established and chemical compounds were screened. Six compounds were positive, but no PTEN increase was obtained. We are currently screening for unpublished small molecules.

Free Research Field

生化学、実験動物学、腫瘍学

Academic Significance and Societal Importance of the Research Achievements

長寿薬の開発は古来からの人類の夢であり、その開発が待たれる。近年PTENを軽度増加せると寿命が延長することが示された。一方PTENは代表的な癌抑制ドライバー分子であるために、その制御機構の解明は癌治療につながる。本研究によって癌の発症抑制をも兼ねそなえた、PTENタンパク質安定性亢進を標的とする長寿薬の開発によって、健康寿命の延長と国民福祉の向上を狙うことが可能となる。