Improvement of Treatment for Urological Cancer by controlling Function of Apotosis-associated molecules using siRNA.

• Project/Area Number: 17390435
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Yamagata University
• Principal Investigator: TOMITA Yoshihiko Yamagata University, Faculty of Medicine, Department of Urology, Professor and Chairman (90237123)
• Co-Investigator(Kenkyū-buntansha): KATO Tomoyuki Yamagata University, Faculty of Med Dpt of Urology, assistant professor (40396560) ; VLADIMIR Bilim Yamagata University, Faculty of Med Dpt of Urology, junior professor (50334686) ; MUTO Akinori Yamagata University, Faculty of Med Dpt of Urology, junior professor (00282228) ; 大地 宏 山形大学, 医学部, 助手 (30302293)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥7,310,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2005: ¥5,100,000 (Direct Cost: ¥5,100,000)
• Keywords: siRNA / Uroloeical Cancer / Anontosis / renal cell cancer / prostate cancer / XIAP / Bcl-2 / 発現ベクター / BCL-2 / CDDP / Docetaxel / NFκ-B / 泌尿器科癌 / ノックダウン

Research Abstract

1. XIAP knock down by siRNA or shRNA.
Designed and introduction of XIAP siRNA or shRNA, decreased production of XIAP transiently or continuously, respectively.
2. Prostate cancer model using DU145
(1) Sensitivity to anticancer drug and knock down of XIAP expression.
Transient suppression of XIAP resulted in increase susceptibility to CDDP, but continuous suppression induced resistant character than parent cell. Upregulation of BCL-2 and NF κ-B were observed in stable transfectants.
(2) Restore the sensitivity by anti-BCL-2 small molecule HA14-1.
HA14-1 cancelled decrease the susceptibility to CDDP.
3. Renal cell cancer model using Caki-1.
(1) XIAP and smac expression in normal kidney and renal cell cancer (RCC).
In normal kidney, smac and XIAP were expressed in renal tubular cells. In 34 RCCs, smac was expressed less frequently, XIAP was strongly expressed in high grade and stage tumor. XIAP and smac were highly expressed in Caki-I and KRC/Y, respectively.
(2) Effect of HA14-1 or smac-mimic synthetic peptide (smac-ant) on cell growth in Caki-1 XIAP lower expresser clone.
HA14-1 alone revealed modest suppression of cell growth but combination with anti-Fas antibody resulted in additional effect-CDDP and smac-ant treatment showed high suppression.
4. In conclusion, XIAP seems to decrease susceptibility to apoptotic stimuli in prostate and renal cell cancer. Suppression using shRNA may not be enough to overcome such character, and additional treatment for reduction of BCL-2 function or further suppression of XIAP using smac-ant might be useful.

Research Products

• [Journal Article] Molecular targeting of BCL-2 overcomes prostate cancer cell adaptation to XIAP gene downregulation. (2008)
  • Author(s): Yuko, Nakano, Vladimir, Bilim, Kaori, Yuuki, Akinori, Muto, Tomoyuki, Kato, Akira, Nagaoka, Yoshihiko, Tomita
  • Journal Title: Prostate Cancer and Prostatic Disease (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis. (2008)
  • Author(s): Bilim, V, Yuuki, K, Itoi, T, Muto, A, Kato, T, Nagaoka, A, Motoyama, T, Tomita, Y.
  • Journal Title: Br. J. Cancer 98 Pages: 941-9
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis (2008)
  • Author(s): Bilim V, Yuuki K, Itoi T, Muto A, Kato T, Nagaoka A, Motoyama T, Tomita Y
  • Journal Title: Br. J. Cancer, 98(5) Pages: 941-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Double inhibition of XLAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis (2008)
  • Author(s): ビリーム, ウラジミル, 他
  • Journal Title: Brit. J Cancer 98巻 Pages: 941-949
  • Peer Reviewed
• [Journal Article] Molecular targeting of Bcl-2 overcomes prostate cancer cell adaptation to XIAP gene downregulation (2008)
  • Author(s): 中野裕子, 他
  • Journal Title: Prostate cancer and prostatic disease
  • Peer Reviewed
• [Journal Article] Molecular targeting of BCL-2 overcomes prostate cancer cell adaptation to XIAP gene downregulation
  • Author(s): Yuko Nakano, Vladimir Bilim, Kaori Yuuki, Akinori Muto, Tomoyuki Kato, Akira Nagaoka,Yoshihiko Tomita
  • Journal Title: Prostate Cancer and Prostatic Disease (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Constitutive suppression of XIAP in DU145 leads to upregulation of Bcl-2 (2008)
  • Author(s): ビリーム, ウラジミル
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-10-04
• [Presentation] Smac-N7 peptide sensitized reanl cancer cell to apoptotic stimuli (2008)
  • Author(s): 内藤整, 他
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-10-04
• [Presentation] Inhibition of GSK-3B activity suppresses the proliferation and induces apoptosis in bladder cancer (2008)
  • Author(s): Sei Naito, Bilim Vladimir, Kaori Suzue, Akinori Muto, Akira Kajinuma, Yuko Kawamura, Hisashi Kawazoe, Tomohiro Shibazaki, Tomoyuki Kato, Akira Nagaoka, Yoshihiko Tomita
  • Organizer: America Urological Association Annual Meeting 2008 Anaheim(cont'd)
  • Place of Presentation: Anaheim, USA
  • Year and Date: 2008-05-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The Smac-N7 cell permeable peptide sensitizes renal cancer cells to anti-cancer drug Cisplatin (2008)
  • Author(s): Tomoyuki Kato, Bilim Vladimir, Kaori Suzue, Akinori Muto, Akira Kajinuma, Yuko Kawamura, Hisashi Kawazoe, Tomohiro Shibazaki, Sei Naito, Akira Nagaoka, Yoshihiko Tomita
  • Organizer: America Urological Association Annual Meeting 2008
  • Place of Presentation: Anaheim, USA
  • Year and Date: 2008-05-18
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 96th Japanese Urological association annual meeting (2008)
  • Author(s): Sei Naito, Bilim Vladimir, Kaori Suzue, Akinori Muto, Akira Kajinuma, Yuko Kawamura Hisashi Kawazoe, Tomohiro Shibazaki, Tomoyuki Kato, Akira Nagaoka, Yoshihiko Tomita
  • Organizer: Yokohama
  • Year and Date: 2008-04-26
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 2. Inhibition of GSK-3B is a potential target to induce apoptosis in Renal Cell Carcinoma (2008)
  • Author(s): Kaori Yuuki, Vladimir Bilim, Andrei V. Ougolkov, Daniel D. Billadeau, Yoshihiko Tomita
  • Organizer: Yokohama
  • Year and Date: 2008-04-26
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Multiple targeting of anti-apoptotic molecules can induce apoptosis in RCC (2008)
  • Author(s): Kaori, Yuuki, Vladimir, Bilim, Tomohiro, Shibazaki, Hisashi, Kawazoe, Teiichi, Motoyama, Yoshihiko Tomita
  • Organizer: 第17回泌尿器科分子・細胞研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-02-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Inbibition of GSK3beta is a potential target to induce apoptosis in Renal Cell Catcinoma(RCC) (2008)
  • Author(s): Vladimir, Bilim, Kaori, Yuuki, Tomohiro, Shibazaki, Hisashi Kawazoe, Teiichi, Motoyama, Yoshihiko, Tomita
  • Organizer: 第17回泌尿器科分子・細胞研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-02-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Multiple targeting of anti-apoptotic molecules can induce apoptosis in RCC (2008)
  • Author(s): Kaori Yuuki, Vladimir Bilim, Tomohiro Shibazaki, Hisashi Kawazoe, Teiichi Motoyama Yoshihiko Tomita
  • Organizer: 17th Urological association of molecular and cellular biology, annual meeting
  • Place of Presentation: Tokyo
  • Year and Date: 2008-02-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Inhibition of GSK3beta is a potential target to induce apoptosis in Renal Cell Carcinoma(RCC) (2008)
  • Author(s): Vladimir Bilim, Kaori Yuuki, Tomohiro Shibazaki, Hisashi Kawazoe, Teiichi Motoyam Yoshihiko Tomita
  • Organizer: 17th Urological association of molecular and cellular biology, annual meeting
  • Place of Presentation: Tokyo
  • Year and Date: 2008-02-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Multiple targeting of anti-apoptotic molecules can induce apoptosis in RCC (2008)
  • Author(s): 結城加織, 他
  • Organizer: 第17回泌尿器科分子・細胞研究会
  • Place of Presentation: 東京都(千代田区)
  • Year and Date: 2008-02-16
• [Presentation] Constitutive suppression of XIAP in DU145 prostate carceinoma cell line leads to resistance to Ciplatinum by upregulation of Bcl-2 (2007)
  • Author(s): 中野裕子・ビリームウラジミル・結城加織・武藤明紀・梶沼陽・川添久・柴崎智宏・内藤整・加藤智幸・長岡明・冨田善彦
  • Organizer: 第45回日本癌治療学会2007
  • Place of Presentation: 京都
  • Year and Date: 2007-10-25
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Constitutive suppression of XIAP in DU145 prostate carcinoma cell line leads to resistance to Cisplatinum by upregulation of Bcl-2 (2007)
  • Author(s): Yuko Nakano, Vladimir Bilim, Kaori Yuuki, Akinori Muto, Akira Kajinuma, Hisashi Kawazoe, Tomohiro Shibazaki, Sei Naito, Tomoyuki Kato, Akira Nagaoka, Yoshihiko Tomita
  • Organizer: ditto
  • Place of Presentation: Kyoto
  • Year and Date: 2007-10-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] SMAC-N7 PEPTIDE WAS MORE POTENT THAN XIAP GENE TARGETING IN SENSITIZING RENAL CANCER CELLS TO APOPTOTIC STIMULI (2007)
  • Author(s): 加藤智幸, 他
  • Organizer: 第45回日本日本癌治療学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2007-10-25
• [Presentation] Constitutive suppression of XIAP in DU145 prostate carcinoma cell line leads to resistance to Cisplatinum by upregulation of Bcl-2 (2007)
  • Author(s): 中野裕子, 他
  • Organizer: 第45回日本日本癌治療学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2007-10-25
• [Presentation] SMAC-N7 PEPTIDE WAS MORE POTENT THAN XIAP GENE TARGETING IN SENSITIZING RENAL CANCER CELLS TO APOPTOTIC STIMULI (2007)
  • Author(s): 加藤智幸・ビリームウラジミル・ 結城加織・武藤明紀・梶沼陽・中野裕子川添久・柴崎智宏・内藤整・長岡明・冨田善彦
  • Organizer: 第45回日本癌治療学会2007
  • Place of Presentation: 京都
  • Year and Date: 2007-10-24
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] SMAC-N7 PEPTIDE WAS MORE POTENT THAN XIAP GENE TARGETING IN SENSITIZING RENAL CANCER CELLS TO APOPTOTIC STIMULI (2007)
  • Author(s): Tomoyuki Kato, Vladimir Bilim, Kaori Yuuki, Akinori Muto, Akira Kajinuma, Yuko Nakano, Hisashi Kawazoe, Tomohiro Shibazaki, Sei Naito, Akira Nagaoka, Yoshihiko Tomita
  • Organizer: 45th Japan society of clinical oncology annual meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2007-10-24
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Inbibition of GSK-3beta Activity Induces Apoptosis in Renal Cell Cancer (2007)
  • Author(s): Vladimir, Bilim, Kaori, Yuuki, AndreiV., Ougolkov, Daniel, D, Billadeau, Yoshihiko, Tomita
  • Organizer: 第66回日本癌学会2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Constitytuve suppression of XTAP in DU145 deads to upregulation of Bcl-2 (2007)
  • Author(s): Kaori, Yuuki, Vladimir, Bilim, Sei, Naito, Tomoyuki, Kato, Yoshihiko, Tomita
  • Organizer: 第66回日本癌学会2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] SMAC-N7 PEPTIDE SENSITIZED RENAL CANCER CELLS TO APOPTOTIC STUMILI (2007)
  • Author(s): Sei, Naito, Kaori, Yuuki, Vladimir, Bilim, Tomoyuki, Kato, Yoshihiko, Tomita
  • Organizer: 第66回日本癌学会2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Inhibition of GSK-3beta Activity Induces Apoptosis in Renal Cell Cancer (2007)
  • Author(s): Vladimir Bilim, Kaori Yuuki, Andrei V. Ougolkov, Daniel D. Billadeau, Yoshihiko Tomita
  • Organizer: 66th Japanese association of cancer research Annual Meeting
  • Place of Presentation: Yokohama
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Constitutive suppression of XIAP in DU145 leads to upregulation of Bcl-2 (2007)
  • Author(s): Kaori Yuuki, Vladimir Bilim, Sei Naito, Tomoyuki Kato, Yoshihiko Tomita
  • Organizer: 66th Japanese association of cancer research Annual Meeting
  • Place of Presentation: Yokohama
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] SMAC-N7 PEPTIDE SENSITIZED RENAL CANCER CELLS TO APOPTOTIC STIMULI (2007)
  • Author(s): Sei Naito, Kaori Yuuki, Vladimir Bilirn, Tomoyuki Kato, Yoshihiko Tomita
  • Organizer: 66th Japanese association of cancer research Annual Meeting
  • Place of Presentation: Yokohama
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The Smac-N7 cell permeable peptide sensitizes renal cancer cells to Cisplatin (2007)
  • Author(s): ビリーム, ウラジミル, 他
  • Organizer: 第95回日本泌尿器科学会総会2007
  • Place of Presentation: 神戸市
  • Year and Date: 2007-04-16
• [Presentation] Constitutive Suppression of XIAP in DU145 Prostte Carcinoma Cell Line Leads to Resistance to Cisplatinum by Upregulation of Bcl-2 (2007)
  • Author(s): 中野裕子, 他
  • Organizer: 第95回日本泌尿器科学会総会2007
  • Place of Presentation: 神戸市
  • Year and Date: 2007-04-16
• [Presentation] The Smac-N7 cell permeable peptide sensitizes renal cancercells to Cisplatin (2007)
  • Author(s): Vladimir, Bilim, Tomoyuki, Kato, Kaori, Yuuki, Toshiyuki, Itoi, Akinori, Muto, Akira, Kajinuma, Yuko, Nakano, Hisashi, Kawazoe, Tomohiro, Shibasaki, Sei, Nito, Akira, Nagaoka, Yoshihiko, Tomita
  • Organizer: 第95回日本泌尿器科学会総会2007
  • Place of Presentation: 神戸
  • Year and Date: 2007-04-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Constitutive Suppression of XIAP in DU145 Prostte Catcinoma Cell Line Leads to Resistance to Cisplatinum by Upregulation of Bcl-2 (2007)
  • Author(s): 川村裕子・ビリーケウラジミル・鈴江加織・内藤整・柴崎智宏・川添久・梶沼陽・武藤明紀・加藤智幸・長岡明・冨田善彦
  • Organizer: 第95回日本泌尿器科学会総会2007
  • Place of Presentation: 神戸
  • Year and Date: 2007-04-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The Smac-N7 cell permeable peptide sensitizes renal cancer cells to Cisplatin (2007)
  • Author(s): Vladimir Bilim,Tomoyuki Kato,Kaori Yuuki,Toshiyuki Itoi,Akinori Muto,Akira Kajinuma,Yuko Nakano,Hisashi Kawazoe,Tomohiro Shibasaki,Sei Nito,Akira Nagaoka,Yoshihiko Tomita
  • Organizer: 95th Japanese Urological association annual meeting
  • Place of Presentation: Kobe
  • Year and Date: 2007-04-15
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Constitutive Suppression of XIAP in DU145 Prostte Carcinoma Cell Line Leads to Resistance to Cisplatinum by Upregulation of Bcl-2 (2007)
  • Author(s): Yuko Kawamura, Vladimir Bilim, Kaori Yuuki, Akinori Muto, Akira Kajinuma, Hisashi Kawazoe, Tomohiro Shibazaki, Sei Naito, Tomoyuki Kato, Ak ra Nagaoka, Yoshihiko Tomita
  • Organizer: 95th Japanese Urological association annual meeting
  • Place of Presentation: Kobe
  • Year and Date: 2007-04-15
  • Description: 「研究成果報告書概要(欧文)」より