RB inactivation in prostate cells increase self-renewal and hormone thrapy refractoriness through activation of mevalonate pathway

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07611
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa Medical University
• Principal Investigator: TOMOSUGI Mitsuhiro 金沢医科大学, 医学部, 助教 (60533429)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: RB / コレステロール / 前立腺がん / SREBP-2 / 去勢抵抗性

Outline of Final Research Achievements

It has been reported that RB increased SREBP-2 (sterol regulatory element-binding protein-2) activity which is a master regulator of the cholesterol synthesis pathway (Shamma A. et al., Cancer Cell, 2009). All steroid hormones are biosynthesized from cholesterol. These findings suggest that loss of function of RB may cause the acquisition of castration resistance in prostate cancer. The following results were obtained from this study. 1. Increased proliferation of Rb1 K.O. LNCaP cells in 10% Charcoal Dextran Treated FBS. 2. In Rb1 K.O. LNCaP cells, protein expression of AR, E2F1, and SREBP-2 is increased in the nuclear fraction. 3. Increased sphere formation in Rb1 K.O. LNCaP cells. 4. Suppression of Rb1 K.O. LNCaP cells growth by statins. These results are expected to clarify a novel regulatory mechanism of RB in prostate cancer. Furthermore, there is possibility that off-label use of statins is effective as a new treatment method for advanced prostate cancer.

Free Research Field

cancer

Academic Significance and Societal Importance of the Research Achievements

前立腺がんの治療後、多くの場合は数年で耐性を獲得し去勢抵抗性前立腺がんへと移行する。去勢抵抗性前立腺がんの70%においてRBがん抑制遺伝子産物の機能が喪失し、そのことが患者の予後不良とよく相関することが報告されている(Schrecengost R., Knudsen KE., Seminars Oncology, 2013)。また、多くのがん腫において、RBの機能喪失は悪性進展を促進することが知られている。本研究結果から新規RB代謝制御機構も解明が期待される。またスタチンの有効性が期待されることから、適応外使用を含む進行前立腺がんの新規治療方法開発が期待できる。