不死化能獲得に関与するp53安定化シグナルの解明とその再構築による癌ゲノム創薬

2010 Fiscal Year Annual Research Report

• Project/Area Number: 21659385
• Research Institution: Kyushu University
• Principal Investigator: 和氣 徳夫 九州大学, 医学研究院, 教授 (60091584)
• Co-Investigator(Kenkyū-buntansha): 小林 裕明 九州大学, 医学研究院, 准教授 (70260700) ; 井上 貴史 九州大学, 大学病院, 助教 (70380417)
• Keywords: 癌細胞老化 / p53 / ゲノム創薬 / 悪性腫瘍

Research Abstract

細胞老化誘導シグナロソームRas/ERα/MDM2/p53/p21の破綻は不死化能獲得に関与する。様々ながん細胞で本シグナロソームを再構築するとがん細胞に老化が誘導される。癌細胞に本シグナロソームを再構築するためSP1阻害剤低濃度Mithramycin(MTH)を用い、MDM2発現抑制及びp53蛋白安定化することを試みた。20nM MTHはp53遺伝子野生型Hec6, HHCIA, KF, OVAS21がん細胞増殖を抑制したが変異型p53遺伝子を持つがん細胞の増殖は抑制しなかった。SubG1及びG0/G1への集積が認められた。p53遺伝子下流のPUMA及びp21発現誘導も観察された。MTH処理後MDHたんぱく発現は抑制されたが、p53蛋白安定化に伴う二次的MDM2蛋白発現誘導が観察された。ヌートマウス皮下移植実験にてMTHは高濃度で軽度な腫瘍形成抑制を示した。一時的p53蛋白の安定化はルシフェレースリポーターアッセイで確認された。低濃度MTHの抗腫瘍効果を増強するためMDM2阻害剤nutlin3との併用を行った。顕著なアポトーシス誘導を伴った腫瘍抑制効果が示された。

Research Products

• [Journal Article] Expression and localization of E-cadherin and catenin in uterine carcinosarcoma (2011)
  • Author(s): Nishimura I, Ohishi Y, Oda Y, Kishimoto J, Yasunaga M, Okuma E, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Virchows Arch Volume: 458(1) Pages: 85-94
  • Peer Reviewed
• [Journal Article] Incidence of postmolar gestational trophoblastic disease in androgenetic moles and the morphological features associated with low risk postmolar gestational trophoblastic disease (2011)
  • Author(s): Kaneki E, Kobayashi H, Hirakawa T, Matsuda T, Kato H, Wake N
  • Journal Title: Cancer Sci Volume: 101(7) Pages: 1717-1721
  • Peer Reviewed
• [Journal Article] Cytoplasmic and stromal expression of laminin 2 chain correlates with infiltrative invasion in ovarian mucinous neoplasms of gastro-intestinal type (2011)
  • Author(s): Okuma E, Ohishi Y, Oda Y, Aishima S, Kurihara S, Nishimural, Yasunaga M, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Oncol Rep Volume: 24(6) Pages: 1569-1576
  • Peer Reviewed
• [Journal Article] Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma (2011)
  • Author(s): Ohishi Y, Oda Y, Kurihara S, Kaku T, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Histopathology Volume: 58(3) Pages: 423-432
  • Peer Reviewed
• [Journal Article] Sentinel node detection with (99m) Tc phytate alone is satisfactory for cervical cancer patients undergoing radical hysterectomy and pelvic lymphadenectomy (2010)
  • Author(s): Ogawa S, Kobayashi H, Amada S, Yahata H, Sonoda K, Abe K, Baba S, Sasaki M, Kaku T, Wake N
  • Journal Title: Int J Clin Oncol Volume: 15(1) Pages: 52-58
  • Peer Reviewed
• [Journal Article] Comparative study of peripheral neurotoxicity after injection of two different paclitaxel formulations in rats (2010)
  • Author(s): Nakamura I, Ichimura E, Kobayashi H, Mashiba H, Nagai H, Ebara K, Hayashi H, Okamoto K, Wake N, Nishikawa K
  • Journal Title: Arzneimittel Forschung Drug Research Volume: 60(4) Pages: 205-209
  • Peer Reviewed
• [Journal Article] A Definitive Haplotype Map as Determined by Genotyping Duplicated Haploid Genomes Finds a Predominant Haplotype Preference at Copy-Number Variation Events (2010)
  • Author(s): Kukita Y, Yahara K, Tahira T, Higasa K, Sonoda M, Yamamoto K, Kato K, Wake N, Hayashi K
  • Journal Title: The American journal of human genetics Volume: 86 Pages: 918-928
  • Peer Reviewed
• [Journal Article] Coincident expression of beta-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas (2010)
  • Author(s): Kurihara S, Oda Y, Ohishi Y, Kaneki E, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Mod Pathol Volume: 23(2) Pages: 225-234
  • Peer Reviewed
• [Journal Article] Endometrial cancer side-population cells show prominent migration and have a potential to differentiate into the mesenchymal cell lineage (2010)
  • Author(s): Kato K, Takao T, Kuboyama A, Tanaka Y, Ohgami T, Yamaguchi S, Adachi S, Yoneda T, Ueoka, Y, Kato Keiji, Hayashi S, Asanoma K, Wake N
  • Journal Title: The American Journal of Pathology Volume: 176(1) Pages: 381-392
  • Peer Reviewed
• [Journal Article] Receptor-binding cancer antigen expressed on SiSo cells induces apoptosis via ectodomain shedding (2010)
  • Author(s): Sonoda K, Miyamoto S, Nakashima M, Wake N
  • Journal Title: Exp Cell Res Volume: 316(11) Pages: 1795-1803
  • Peer Reviewed
• [Journal Article] Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers (2010)
  • Author(s): Ohgami T, Kato K, Kobayashi H, Sonoda K, Inoue T, Yamaguchi S, Yoneda T, Wake N
  • Journal Title: Cancer Sci Volume: 101(6) Pages: 1387-1395
  • Peer Reviewed
• [Journal Article] Three cases of acute fatty liver of pregnancy : Postpartum clinical course depends on interval between onset of symptoms and termination of pregnancy (2010)
  • Author(s): Aso K, Hojo S, Yumoto Y, Fukushima K, Miyazaki M, Kotoh K, Wake N
  • Journal Title: J Matern Fetal Neonatal Med Volume: 23(9) Pages: 1047-1049
  • Peer Reviewed