Development of therapeutics targeting the Vav3 oncogene for castration-resistant prostate cancer

• Project/Area Number: 24592397
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Oita University
• Principal Investigator: NOMURA TAKEO 大分大学, 医学部, 客員研究員 (40347034)
• Co-Investigator(Kenkyū-buntansha): MIMATA Hiromitsu 大分大学, 医学部, 教授 (60219714)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 去勢抵抗性 / 低酸素 / Vav3 / アポトーシス / アンドロゲン受容体 / EMT

Outline of Final Research Achievements

We examined Vav3 siRNA effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH). Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased Bcl-2 phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis through Bad dephosphorylation. Xenograft tumor growth was inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3 and docetaxel produced a greater effect than docetaxel alone.
Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer.

Research Products

• [Journal Article] The Vav3 oncogene enhances the malignant potential of prostate cancer cells under chronic hypoxia. (2014)
  • Author(s): Hirai K, Nomura T, Yamasaki M, Inoue T, Narimastu T, Nakada C, Tsukamoto Y, Matsuura K, Sato F, Moriyama M, Mimata H.
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: 32 Pages: 101-109
  • Peer Reviewed
• [Journal Article] 長期低酸素環境下前立腺癌細胞増殖機構解明と新治療法 (2014)
  • Author(s): 野村威雄、山崎六志、三股浩光
  • Journal Title: 日本臨床 Volume: 72 Pages: 2136-2140
• [Journal Article] Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia. (2013)
  • Author(s): Nomura T, Yamasaki M, Hirai K, Inoue T, Sato R, Matsuura K, Moriyama M, Sato F, Mimata H.
  • Journal Title: Mol Cancer. Volume: 12 Issue: 1 Pages: 27-27
  • DOI: 10.1186/1476-4598-12-27
  • Peer Reviewed
• [Presentation] Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia in vitro and in vivo (2014)
  • Author(s): Nomura T, Yamasaki M, Hirai K, Inoue T, Sato R, Sato F, Mimata H
  • Organizer: アメリカ泌尿器科学会総会
  • Place of Presentation: Orange County Convention Center,Orlando, アメリカ合衆国
  • Year and Date: 2014-05-16 – 2014-05-21