Targeting the Serine Synthesis Pathway as a Potential Novel Bladder Cancer Therapy and the elucidation of its Expression Mechanism

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K18146
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Kagoshima University
• Principal Investigator: OSAKO Yoichi 鹿児島大学, 医歯学総合研究科, 客員研究員 (60793354)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 膀胱癌

Outline of Final Research Achievements

We previously identified that PHGDH, which converts glycolytic substrates to the serine synthesis pathway, is activated in treatment-resistant cancers, and we reported that metabolic reprogramming contributes to the acquisition of treatment resistance. On the other hand, in a clinical statistical analysis of bladder cancer, PHGDH expression was correlated with malignancy, and PHGDH was found to be an independent poor prognostic factor. Therefore, the purpose of this study was to elucidate the mechanism of PHGDH expression as well as to explore the possibility of novel therapeutic strategies targeting PHGDH in bladder cancer.

Free Research Field

泌尿器癌

Academic Significance and Societal Importance of the Research Achievements

我々は、膀胱癌細胞株を用いて、PHGDHのsi-RNAや阻害剤を投与したところアポトーシスを介した腫瘍抑制効果をin vitro並びにin vivoにおいて示した。更にPHGDHの発現にメチル化が関係していることを初めて示した。これらの結果より、膀胱癌におけるPHGDHを標的とした新規治療の可能性とPHGDHの発現機序の一端を報告することができた。更に、当科で樹立したgemcitabine並びにcisplatin耐性膀胱癌細胞株を調べたところ、それらの耐性細胞においてPHGDHの発現が亢進していることが確認され、膀胱癌の治療抵抗性獲得に代謝リプログラミングが寄与することが示唆された。