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

• Project/Area Number: 21659385
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• 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) ; 谷口 秀一 九州大学, 大学病院, 助教 (70452711)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥3,100,000 (Direct Cost: ¥3,100,000); Fiscal Year 2010: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2009: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: 癌細胞老化 / p53 / ゲノム創薬 / 悪性腫瘍 / がん細胞老化 / MDM2 / ROS / p21

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
  • NAID: 10026595031
  • 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
  • NAID: 10027201656
  • 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
  • NAID: 120002239171
  • 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
  • NAID: 120005227172
  • 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
  • NAID: 10026593277
  • 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
• [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 23(2) Pages: 225-34
• [Journal Article] The Phenotypic and Metabolic of Characteristics of Neutrophils in Normal Pregnancy and Preeclampsia (2009)
  • Author(s): Tsukimori K, Fukushima K, Nakano H, Wake N
  • Journal Title: Current immunology reviews 5(3) Pages: 243-248
• [Journal Article] Improvement in the outcome of patients with antenatally diagnosed congenital diaphragmatic hernia using gentle ventilation and circulatory stabilization (2009)
  • Author(s): Masumoto K, Teshiba R, Esumi G, Nagata K, Takahata Y, Hikino S, Hara T, Hojo S, Tsukimori K, Wake N, Kinukawa N, Taguchi T
  • Journal Title: Pediatric surgery international 25(6) Pages: 487-492
  • NAID: 10029305718
• [Journal Article] Three-dimensional power Doppler sonography in the diagnosis of a cystic sacrococcygeal teratoma mimicking a meningomyelocele : A case report (2009)
  • Author(s): Sugitani M, Morokum S, Hidaka N, Kinoshita Y, Taguchi T, Tsukimori K, Wake N
  • Journal Title: Journal of clinical ultrasound 37(7) Pages: 410-410
• [Journal Article] Immunohistochemical characterization of mullerian mucinous borderline tumors : possible histogenetic link with serous borderline tumors and low-grade endometrioid tumors (2009)
  • Author(s): Yasunaga M, Ohishi Y, Oda Y, Misumi M, Iwasa A, Kurihara S, Nishimura I, Okuma E, Kobayashi H, Wake N, Tsuneyoshi M
  • Journal Title: Human Pathorogy 40(7) Pages: 965-974
• [Journal Article] Homebox gene HOPX is epigenetically silenced in human uterine endometrial cancer cells by inhibiting serum response factor (2009)
  • Author(s): Yamaguchi S, Asanoma K, Takao T, Kato K, Wake, N.
  • Journal Title: International Journal of Cancer 124 Pages: 2257-2588
• [Journal Article] The Level of RCAS1 Expression Is Inversely Correlated With the Number of Vitamin-Positive Stromal Cells in Epithelial Overian Cancer (2009)
  • Author(s): Sonoda K, Miyamoto S, Kobayashi H, Ogawa S, Okugawa K, Taniguchi S, Wake N
  • Journal Title: International Journal of Gynecologica Cancer 19(5) Pages: 838-843
• [Journal Article] Preload index of the inferior vena cava as a possible predictive marker of hydropic changes in fetuses with Ebstein anomaly (2009)
  • Author(s): Hidaka N, Sugitani M, Fujita Y, Fukushima K, Tsukimori K, Wake, N.
  • Journal Title: J Ultrasound in Medicine 2009 28(10) Pages: 1369-1374
• [Journal Article] Prenatal diagnosis of trisomy 16 mosaicism manifested as pulmonary artery stenosis (2009)
  • Author(s): Hidaka N, Yamamoto N, Tsukimori K, Hojo S, Suzuki S, Wake N
  • Journal Title: J Clin Ultrasound 37(2) Pages: 107-11
• [Journal Article] Can we diagnose invasive cervical cancer during pregnancy as precise as in nonpregnant women? : maternal and perinatal outcome in pregnancies complicated with cervical cancers (2009)
  • Author(s): Fukushima K, Ogawa S, Tsukimori K, Kobayashi H, Wake N
  • Journal Title: Int J Gynecol Cancer 19(8) Pages: 1439-45
• [Journal Article] Level of reactive oxygen species induced by p21Waf1/CIP1 is critical for the determination of cell fate (2009)
  • Author(s): Inoue T, Kato K, Kato H, Asanoma K, Kuboyama A, Ueoka Y, Yamaguchi S, Ohgami T, Wake N
  • Journal Title: Cancer Science 100(7) Pages: 1275-83
  • NAID: 10027192262