2001 Fiscal Year Annual Research Report

細胞がん化のシグナル伝達の解析と抗がん剤リードの探索

Research Project

Project/Area Number	12217163
Research Institution	National Institute of Infectious Diseases
Principal Investigator	上原至雅国立感染症研究所, 生物活性物質部, 部長 (50160213)
Co-Investigator(Kenkyū-buntansha)	野口耕司国立感染症研究所, 生物活性物質部, 研究員 (80291136) 深澤秀輔国立感染症研究所, 生物活性物質部, 室長 (10218878)
Keywords	MEK阻害剤 / U0126 / 足場非依存性増殖 / apoptosis / rapamycin / anoikis / anicequol / ERK
Research Abstract	がん細胞の足場非依存性増殖を選択的に抑制する物質を約50種のヒトがん細胞パネルを用いて検索した。大腸がん、乳がん細胞などの中にMEK阻害剤U0126により、浮遊状態での増殖が、接着状態での増殖よりも強く抑えられるものがあった。乳がんの2株ではU0126で処理すると非接着状態でのみapoptosisによる細胞死が誘導されたが、接着状態では細胞死は観察されなかった。即ちこれらの細胞は、U0126により正常細胞様のanoikis感受性が誘導された。シグナル伝達分子の活性化状態を調べると、U0126はMEK-ERK経路に加え、mTOR-p70S6Kの経路を阻害していた。anoikis感受性が誘導されない細胞では、U0126によりERKの活性化は抑制されたが、p70S6Kはほとんど影響を受けなかったことから、p70S6K経路のU0126に対する感受性が、anoikis感受性の誘導の重要な決定要因の一つであることが示唆された。また、がん細胞足場非依存性増殖抑制物質anicequolの作用を解析し、PI3Kからp70S6kを介するシグナル伝達経路の活性化を介し足場非存在下の細胞においてのみapoptosisを誘導することを見出した。

Research Products

(9 results)

All Other

All Publications (9 results)

[Publications] Noguchi, K.: "ASK1-signaling promotes c-Myc protein stability during apoptosis"Biochem Biophys Res Commun.. 281. 1313-1320 (2002)
[Publications] Hori, H.: "Biosynthesis of hibarimicins. I. ^<13>C-Labeling experiments"J.Antibiotics. 55. 46-52 (2002)
[Publications] Kajiura, T.: "Biosynthesis of hibarimicins. II. Elucidation of biosynthetic pathway by cosynthesis using blocked mutants"J.Antibiotics. 55. 53-60 (2002)
[Publications] Igarashi, Y.: "Biosynthesis of hibarimicins. III. Structures of new hibarimicin-related metabolites produced by blocked mutants"J.Antibiotics. 55. 61-70 (2002)
[Publications] Cho, S.I.: "Effects of hibarimicins and hibarimicin-related compounds produced by Microbispora on v-src kinase activity and growth and differentiation of human myeloid leukemia HL-60 cells"J.Antibiotics. (in press).
[Publications] Murakami, Y.: "A mammalian two-hybrid screening system for inhibitors of interaction between HIV Nef and the cellular tyrosine kinase Hck"Antiviral Res.. (in press).
[Publications] Kitanaka, C.: "Increased Ras expression and caspase-independent neuroblastoma cell death : possible mechanism of spontaneous neuroblastoma regression"J.Natl.Cancer Inst.. (in press).
[Publications] Fukazawa, H.: "Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase(MEK)inhibitors restore anoikis-sensitivity in human breast cancer cell lines with constitutively activated Extracellular Signal-regulated Kinase(ERK)pathway"Mol. Cancer Therapeut. (in press).
[Publications] Igarashi, Y.: "Anicequol, a novel inhibitor for anchorage-independent growth of tumor cells from Penicillium sp. TP-F0213"J.Antibiotics. (in press).

2001 Fiscal Year Annual Research Report

細胞がん化のシグナル伝達の解析と抗がん剤リードの探索

Principal Investigator

上原 至雅 国立感染症研究所, 生物活性物質部, 部長 (50160213)

Research Products

[Publications] Noguchi, K.: "ASK1-signaling promotes c-Myc protein stability during apoptosis"Biochem Biophys Res Commun.. 281. 1313-1320 (2002)

[Publications] Hori, H.: "Biosynthesis of hibarimicins. I. ^<13>C-Labeling experiments"J.Antibiotics. 55. 46-52 (2002)

[Publications] Kajiura, T.: "Biosynthesis of hibarimicins. II. Elucidation of biosynthetic pathway by cosynthesis using blocked mutants"J.Antibiotics. 55. 53-60 (2002)

[Publications] Igarashi, Y.: "Biosynthesis of hibarimicins. III. Structures of new hibarimicin-related metabolites produced by blocked mutants"J.Antibiotics. 55. 61-70 (2002)

[Publications] Cho, S.I.: "Effects of hibarimicins and hibarimicin-related compounds produced by Microbispora on v-src kinase activity and growth and differentiation of human myeloid leukemia HL-60 cells"J.Antibiotics. (in press).

[Publications] Murakami, Y.: "A mammalian two-hybrid screening system for inhibitors of interaction between HIV Nef and the cellular tyrosine kinase Hck"Antiviral Res.. (in press).

[Publications] Kitanaka, C.: "Increased Ras expression and caspase-independent neuroblastoma cell death : possible mechanism of spontaneous neuroblastoma regression"J.Natl.Cancer Inst.. (in press).

[Publications] Fukazawa, H.: "Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase(MEK)inhibitors restore anoikis-sensitivity in human breast cancer cell lines with constitutively activated Extracellular Signal-regulated Kinase(ERK)pathway"Mol. Cancer Therapeut. (in press).

[Publications] Igarashi, Y.: "Anicequol, a novel inhibitor for anchorage-independent growth of tumor cells from Penicillium sp. TP-F0213"J.Antibiotics. (in press).

上原至雅国立感染症研究所, 生物活性物質部, 部長 (50160213)