2000 Fiscal Year Annual Research Report

がん細胞の酸素・栄養飢餓抵抗性の機構とその進展における研究

Research Project

Project/Area Number	12213153
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
Principal Investigator	江角浩安国立がんセンター, 研究所支所, 支所長 (70160364)
Keywords	膵臓がん / 栄養飢餓 / PKB / Akt / AMPK / P13キナーゼ / 耐性
Research Abstract	膵臓がんを含め多くの未分化ながんでは、グルコースをはじめとする栄養飢餓に顕著な耐性を示すことを見出した。この耐性のメカニズムを明らかにする為、各種の試みをした。PKB/AKtのantisense vectorを膵臓がん細胞PANC-1に安定導入すると、Akt1,Akt2のautisense RNA発現ヴェクター導入細胞では、顕著な栄養飢餓耐性の減弱が見られた。また、耐性を解除する薬剤troglitazone,LY294002ともにAktの燐酸化を阻害することがわかった。更に、RNC-1細胞をグルコース欠乏培地の中で培養すると、数分以内にRNB/AktのSer473のリン酸化が起こり、このリン酸化はP13キナーゼ依存症であった。PKB/Aktが栄養飢餓耐性に関与していると考えられる。細胞が如何にして栄養飢餓を検知するのかを検討する過程で、5'AMP-activated蛋白質リン酸化酵素の栄養飢餓耐性への関与が明らかになった。同様にAMP activated protein kinase antisense vectorを導入すると、耐性がほぼ完全に解除されたが、通常の培地での増殖速度には全く影響を与えなかった。しかし、これらの細胞を、ヌードマウスの皮下に移植するとAMPKα1とα2 antisenRNA expression vectorを安定導入した細胞では顕著な腫瘍形成能の抑制が見られた。栄養飢餓耐性へのAMPKの関与が明らかになったと共に、腫瘍形成に栄養飢餓耐性が関与することを強く示唆した。

Research Products

(10 results)

All Other

All Publications (10 results)

[Publications] Kimura,H.,Esumi,H. et al: "Hypoxia response element of the human vascular endothelial growth factor gene mediates Transcriptional regulation by nitric oxide : control of hypoxia-inducible factor-1 activity by nitric oxide"BLOOD. 95. 189-197 (2000)
[Publications] Matsumi H,Esumi H, et al: "Regulation of nitric oxide synthase to promote cytostasis in ovarian follicular development."Biol Reprod. 63. 141-146 (2000)
[Publications] Bermont,L.,Esumi,H. et al: "Regulation of vascular endothelial groowth factor espression by Insulin-like Growth Factor-1 in endometrial adenocarcinoma cells"Intl J Cancer. 85. 117-128 (2000)
[Publications] Muto,M.,Esumi,H. et al: "Association of aldehyde dehydrogenase 2 gene polymorphism with multiple esophageal dysplasia in head and neck cancer patients"GUT. 47. 256-261 (2000)
[Publications] Sakurazawa,N.,Esumi,H. et al: "Instability of X-chromosome methylation in aberrant crypt foci of the human colon"Cancer Research. 60. 3165-3169 (2000)
[Publications] Muto,M.,Esumi H. et al: "Acetaldehyde production by Non-pathogenic Neisseria in Human Oral Microflora"Intl J Cancer. 88. 342-350 (2000)
[Publications] Soisungwan Satarug,Jason R.Baker.,paul E.B.Reilly.,Esumi H.,Micheal R.Moore.: "Evidence for a Synergistic Interaction between Cadmium and Endotoxin Toxicity and for Nitric Oxide and Cadmium Displacement of Metals in the Kidney"NITRIC OXIDE. 4. 431-440 (2000)
[Publications] Izuishi,K.,Kato,K.,Ogura,T.,Kinoshita,T.,Esumi,H.: "Remarkable Tolerance of Tumor Cells to Nutrient Deprivation"Possible New Biochemical Target for Cancer Therapy,Cancer Research. 60. 6201-7 (2000)
[Publications] Hideo Kimura.,Alessandro Weisz.,Tsutomu Ogura.,Yoshiaki Hitomi.,Yukiko Kurashima.,Kouichi Hashimoto.,Fulvio D'Acquisto.,Masatoshi Makuuchi.,Esumi H.: "Identification of Hypoxia-Inducible Factor-1 (HIF-1) Ancillary Sequence and Its Function in Vascular Endothelial Growth Factor Gene Induction by Hypoxia and Nitric Oxide"J Biol Chem . (in press).
[Publications] Laurent Bermont., Fr d rique Lamielle., Fabrice Lorchel.,Sylvie Fauconnet.,Esumi H.,: "Alessandro Weisz., and G rard L. Adessi Insulin upregulates VEGF and stabilizes its messengers in endmentrial denocarcinoma cells "J.Clin Endocrinol. Metab. (in press).

2000 Fiscal Year Annual Research Report

がん細胞の酸素・栄養飢餓抵抗性の機構とその進展における研究

Principal Investigator

江角 浩安 国立がんセンター, 研究所支所, 支所長 (70160364)

Research Products

[Publications] Kimura,H.,Esumi,H. et al: "Hypoxia response element of the human vascular endothelial growth factor gene mediates Transcriptional regulation by nitric oxide : control of hypoxia-inducible factor-1 activity by nitric oxide"BLOOD. 95. 189-197 (2000)

[Publications] Matsumi H,Esumi H, et al: "Regulation of nitric oxide synthase to promote cytostasis in ovarian follicular development."Biol Reprod. 63. 141-146 (2000)

[Publications] Bermont,L.,Esumi,H. et al: "Regulation of vascular endothelial groowth factor espression by Insulin-like Growth Factor-1 in endometrial adenocarcinoma cells"Intl J Cancer. 85. 117-128 (2000)

[Publications] Muto,M.,Esumi,H. et al: "Association of aldehyde dehydrogenase 2 gene polymorphism with multiple esophageal dysplasia in head and neck cancer patients"GUT. 47. 256-261 (2000)

[Publications] Sakurazawa,N.,Esumi,H. et al: "Instability of X-chromosome methylation in aberrant crypt foci of the human colon"Cancer Research. 60. 3165-3169 (2000)

[Publications] Muto,M.,Esumi H. et al: "Acetaldehyde production by Non-pathogenic Neisseria in Human Oral Microflora"Intl J Cancer. 88. 342-350 (2000)

[Publications] Soisungwan Satarug,Jason R.Baker.,paul E.B.Reilly.,Esumi H.,Micheal R.Moore.: "Evidence for a Synergistic Interaction between Cadmium and Endotoxin Toxicity and for Nitric Oxide and Cadmium Displacement of Metals in the Kidney"NITRIC OXIDE. 4. 431-440 (2000)

[Publications] Izuishi,K.,Kato,K.,Ogura,T.,Kinoshita,T.,Esumi,H.: "Remarkable Tolerance of Tumor Cells to Nutrient Deprivation"Possible New Biochemical Target for Cancer Therapy,Cancer Research. 60. 6201-7 (2000)

[Publications] Laurent Bermont., Fr d rique Lamielle., Fabrice Lorchel.,Sylvie Fauconnet.,Esumi H.,: "Alessandro Weisz., and G rard L. Adessi Insulin upregulates VEGF and stabilizes its messengers in endmentrial denocarcinoma cells "J.Clin Endocrinol. Metab. (in press).

江角浩安国立がんセンター, 研究所支所, 支所長 (70160364)