Functional analysis of autophagy in PTEN/Atg7 double knockout mouse prostate cancer

• Project/Area Number: 26670707
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Kinki University
• Principal Investigator: UEMURA Hirotsugu 近畿大学, 医学部, 教授 (90213397)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: オートファジー / 前立腺癌 / マウスモデル / ノックアウトマウス / PTEN / Cre-LoxPシステム / 去勢抵抗性がん / Atg7 / Atg-7

Outline of Final Research Achievements

We had previously developed a conditional knockout mouse model in which homozygous deletion of PTEN lead to the stage-specific development of invasive adenocarcinoma. To determine the effect of defective autophagy on prostate cancer progression, we generated prostate-specific conditional double knockout mice harboring both inactivated PTEN and ATG7, a key regulator for the formation of autophagosomes. We show that inhibition of autophagy by the conditional inactivation of ATG7, a gene essential for autophagosome formation, does not contribute to tumor initiation. We also show that simultaneous inactivation of ATG7 significantly suppresses PTEN-deficient prostate cancer progression and improves survival.

Research Products

• [Journal Article] Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer. (2015)
  • Author(s): De Velasco MA, Kura Y, Yoshikawa K, Nishio K, Davies BR, Uemura H.
  • Journal Title: Oncotarget. Volume: 7 Issue: 13 Pages: 15959-15976
  • DOI: 10.18632/oncotarget.7557
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer. (2015)
  • Author(s): Yamamoto Y, De Velasco MA, Kura Y, Nozawa M, Hatanaka Y, Oki T, Ozeki T, Shimizu N, Minami T, Yoshimura K, Yoshikawa K, Nishio K, Uemura H.
  • Journal Title: J Transl Med. Volume: 13 Issue: 1 Pages: 150-162
  • DOI: 10.1186/s12967-015-0509-x
  • Peer Reviewed
• [Presentation] マウス前立腺癌モデルを用いたAKT阻害薬 AZD 5356の抗腫瘍効果 (2015)
  • Author(s): Uemura H., Kura Y., Shimizu N. et al.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋コングレスセンター
  • Year and Date: 2015-10-09
• [Presentation] Chloroquine demonstrates limited effectiveness in an autochthonous preclinical model of prostate cancer (2015)
  • Author(s): Kura Y., De Velasco M., Uemura H. et al.
  • Organizer: AACR
  • Place of Presentation: フィラデルフィア, アメリカ
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] Effects of long-term chloroquine chemotherapy in a preclinical model of PTEN-deficier (2015)
  • Author(s): Yoshikawa K., De Velasco M., Uemura H. et al
  • Organizer: AACR
  • Place of Presentation: フィラデルフィア, アメリカ
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] Autophagy in prostate tumorigenes and its clinical implications (2014)
  • Author(s): デベラスコ マルコ、倉由吏恵、畑中祐二、山本 豊、清水信貴、吉村一宏、野澤昌弘、吉川和宏、西尾和人、植村天受
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 前立腺癌におけるオートファジーの生物学的意義 (2014)
  • Author(s): デベラスコ マルコ、倉由吏恵、安藤直美、福島恵美子、畑中祐二、山本 豊、清水信貴、吉村一宏、野澤昌弘、吉川和宏、西尾和人、植村天受
  • Organizer: 第102回日本泌尿器科学会総会
  • Place of Presentation: 神戸市（神戸国際会議場・神戸国際展示場・神戸ポートピアホテル）
  • Year and Date: 2014-04-24 – 2014-04-27
• [Presentation] The role of autophagy in prostate tumorigenesis and its therapeutic implications (2014)
  • Author(s): M.A. De Velasco, Y. Kura, N. Ando, E. Fukushima, Y. Hatanaka, Y. Yamamoto, N. Shimizu, K. Yoshimura, M. Nozawa, K. Yoshikawa, K. Nishio and H. Uemura
  • Organizer: AACR
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09