The metabolic function of RB in controlling mevalonate (MVA) pathway regulates tumor progression

• Project/Area Number: 25830076
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: SASAKI Nobuari 金沢大学, がん進展制御研究所, 博士研究員 (40415170)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: コレステロール / メバロン酸経路 / 悪性進展 / 細胞内ROS / RB / 前立腺がん / 癌幹細胞 / コレステロールエステル / retinoblastoma / がん幹細胞 / ROS / cholesterol / mevalonate pathway / cancer stem cell

Outline of Final Research Achievements

Recent advances in cancer metabolism have revealed that metabolic abnormalities in cancer cells are closely related to enhanced cell proliferation and malignant progression of a number of tumors.
Mutations in Retinoblastoma (RB) gene are found at the initiation of limited human cancers, whereas RB protein inactivation is frequently found in much wider variety of cancers mainly during their progression. These findings suggest that RB exerts more roles than previously thought. Here we show that RB affects transcription of many enzymes involved in Mevalonate (MVA) pathway. We demonstrate that RB depletion in prostate cancer cells induces some of typical malignant features including tumor sphere forming-activity and hormone-refractory growth. Cholesterol and its derivatives generated by MVA pathway contribute to these phenotypes through modifying cellular ROS level.
These results indicate that RB regulates cancer progression through the metabolic function in controlling MVA pathway.

Research Products

• [Journal Article] Undifferentiated State Induced by Rb-P53 Double Inactivation in Mouse Thyroid Neuroendocrine Cells and Embryonic Fibroblasts (2015)
  • Author(s): Kitajima S, Kohno S, Kondoh A, Sasaki N, Nishimoto Y, Li F, Mohammed MS, Muranaka H, Nagatani N, Suzuki M, Kido Y, Takahashi C
  • Journal Title: STEM CELLS Volume: - Issue: 5 Pages: 1657-1669
  • DOI: 10.1002/stem.1971
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ATM mediates pRB function to control DNMT1 protein stability and DNA methylation. (2013)
  • Author(s): Shamma A, Suzuki M, Hayashi N, Kobayashi M, Sasaki N, Nishiuchi T, Doki Y, Okamoto T, Kohno S, Muranaka H, Kitajima S, Yamamoto K, Takahashi C
  • Journal Title: Molecular and Cellular Biology Volume: 33 Issue: 16 Pages: 3113-3124
  • DOI: 10.1128/mcb.01597-12
  • NAID: 120005312327
  • Peer Reviewed
• [Presentation] RBによるメバロン酸経路を介したがん悪性進展制御機構 (2015)
  • Author(s): 佐々木信成, 村中勇人, 北嶋俊輔, 河野晋, Shamma A, 髙橋智聡
  • Organizer: 日本癌学会シンポジウム / 共同利用・共同研究拠点シンポジウム
  • Place of Presentation: 石川県立音楽堂交流ホール
  • Year and Date: 2015-01-21 – 2015-01-22
• [Presentation] がん抑制遺伝子RBによるSREBP-1の制御とがんにおける役割の解析 (2015)
  • Author(s): 村中勇人, 北嶋俊輔, 佐々木信成, 河野晋, 林昭夫, 多田秀明, 丹下正一郎, 鈴木健人, Shamma A, 髙橋智聡
  • Organizer: 日本癌学会シンポジウム / 共同利用・共同研究拠点シンポジウム
  • Place of Presentation: 石川県立音楽堂交流ホール
  • Year and Date: 2015-01-21 – 2015-01-22
• [Presentation] The metabolic function of RB in controlling mevalonate (MVA) pathway regulates tumor progression (2015)
  • Author(s): Sasaki N, Kitajima S, Muranaka H, Shamma A, Kohno S, Takahashi C
  • Organizer: Keyston Symposia
  • Place of Presentation: Fairmont Hotel Vancouver, Vancouver, Canada
  • Year and Date: 2015-01-13 – 2015-01-18
• [Presentation] RBによるメバロン酸経路を介したがん悪性進展制御機構 (2014)
  • Author(s): 佐々木信成, 村中勇人, 北嶋俊輔, 河野晋, Shamma A, 髙橋智聡
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜 パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] がん抑制遺伝子RBによるSREBP-1の制御とがんにおける役割の解析 (2014)
  • Author(s): 村中勇人, 北嶋俊輔, 佐々木信成, 河野晋, 吉田晶代, 丹下正一朗, 鈴木健之, 林昭夫, 多田秀昭, Shamma A, 髙橋智聡
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜 パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] RBの中心代謝制御機能 (2014)
  • Author(s): 河野晋, 北嶋俊輔, 吉田晶代, 鈴木佐和子, 田中知明, 佐々木信成, 村中勇人, 髙橋智聡
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜 パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] The metabolic function of RB in controlling mevalonate (MVA) pathway and tumor progression (2014)
  • Author(s): Sasaki N, Muranaka H, Kitajima S, Kohno S, Shamma A and Takahashi C
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜 パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] RBによるメバロン酸経路を介したがん悪性進展制御機構 (2014)
  • Author(s): 佐々木信成, 村中勇人, 北嶋俊輔, 河野晋, Shamma A, 髙橋智聡
  • Organizer: 平成26年度 がん若手研究者ワークショップ
  • Place of Presentation: 蓼科 蓼科グランドホテル滝の湯
  • Year and Date: 2014-09-03 – 2014-09-06
• [Presentation] がん抑制遺伝子RBによるSREBP-1の制御とがんにおける役割の解析 (2014)
  • Author(s): 村中勇人, 北嶋俊輔, 佐々木信成, 河野晋, Shamma A, 髙橋智聡
  • Organizer: 平成26年度 がん若手研究者ワークショップ
  • Place of Presentation: 蓼科 蓼科グランドホテル滝の湯
  • Year and Date: 2014-09-03 – 2014-09-06
• [Presentation] RB不活性化によって誘導されるがん幹細胞様未分化状態におけるPgam2の役割 (2014)
  • Author(s): 河野晋, 北嶋俊輔, 佐々木信成, 村中勇人, 鈴木佐和子, 田中知明, 岡橋伸幸, 松田史生, 清水浩, 髙橋智聡
  • Organizer: 第2回がんと代謝研究会
  • Place of Presentation: 東京 東京理科大学葛飾キャンパス 図書館大ホール
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] The metabolic function of RB in controlling mevalonate (MVA) pathway and cancer cells (2014)
  • Author(s): Nobunari Sasaki, Chiaki Takahashi
  • Organizer: International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discovery in Academics
  • Place of Presentation: 金沢 エクセルホテル東急
• [Presentation] RB controls lipid metabolism in cancer cells (2014)
  • Author(s): Hayato Muranaka, Shunsuke Kitajima, Nobunari Sasaki, Susumu Kohno, Awad Shamma, Chiaki Takahashi
  • Organizer: International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discovery in Academics
  • Place of Presentation: 金沢 エクセルホテル東急
• [Presentation] Role of RB tumor suppressor gene in central carbon metabolism (2014)
  • Author(s): Susumu Kohno, Shunsuke Kitajima, Sawako Suzuki, Tomoaki Tanaka, Nobuyuki Okahashi, Fumio Matsuda, Hiroshi Shimizu, Nobunari Sasaki, Hayato Muranaka, Chiaki Takahashi
  • Organizer: International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discovery in Academics
  • Place of Presentation: 金沢 エクセルホテル東急
• [Presentation] RBの中心炭素代謝調節機能 (2013)
  • Author(s): 河野晋、北嶋俊輔、佐々木信成、村中勇人、鈴木佐和子、田中知明、岡橋信幸、松田史生、清水浩、高橋智聡
  • Organizer: 第1回がんと代謝研究会
  • Place of Presentation: 鶴岡 慶應義塾大学先端生命科学研究所
• [Presentation] The role of RB tumor suppressor gene in central carbon metabolism (2013)
  • Author(s): Susumu Kohno, Shunsuke Kitajima, Nobunari Sasaki, Hayato Muranaka, Chiaki Takahashi
  • Organizer: Third International Rb Meeting
  • Place of Presentation: Monterey, CA. USA
• [Presentation] がん抑制遺伝子RBの代謝調節機能 (2013)
  • Author(s): 河野晋、北嶋俊輔、佐々木信成、村中勇人、高橋智聡
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜 パシフィコ横浜
• [Presentation] The pRB-ATM-DNMT1 nexus is a novel pathway to the epigenetic control of cancer progression (2013)
  • Author(s): Awad Shamma, Naoyuki Hayashi, Nobunari Sasaki, Chiaki Takahashi
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜 パシフィコ横浜
• [Presentation] RBによるメバロン酸経路の制御とがん幹細胞における役割 (2013)
  • Author(s): 佐々木信成、高橋智聡
  • Organizer: 平成25年度がん若手ワークショップ
  • Place of Presentation: 蓼科 蓼科グランドホテル滝の湯
• [Presentation] The metabolic function of RB tumor suppressor gene (2013)
  • Author(s): Susumu Kohno, Shunsuke Kitajima, Nobunari Sasaki, Hayato Muranaka, Chiaki Takahashi
  • Organizer: American Association for Cancer Research Annual Meeting 2013
  • Place of Presentation: Washington, DC. USA
• [Remarks] 金沢大学がん進展制御研究所 腫瘍分子生物学研究分野 高橋智聡研究室
  • URL: http://omb.w3.kanazawa-u.ac.jp/