Serine and matrix metalloproteinase inhibition for malignant astrocytoma therapy.

• Project/Area Number: 11671406
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Fukuoka University
• Principal Investigator: YAMAMOTO Masaaki Sch.of Med.Fukuoka University, Assist.Prof., 医学部, 講師 (80240125)
• Project Period (FY): 1999 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: malignant astrocytoma / uPA / gelatinase / IRP / NF-kB / invasion / TNF-alpha / RAP / 蛋白分解酵素 / NF-kB

Research Abstract

In this study, we investigated that the role of NF-kB for regulation of the expression of urokinase-type plasminogen activator (uPA) and signal transduction in tumor necrosis factor-α (TNF-α)-induced cytotoxicity. We found that NF-kB (p50 and p65 subunits) is activated in human astrocytomas in vivo and in vitro, which contributed the overexpression of uPA.Activation of nuclear factor-κB (NF-κB) protects against TNF-α-induced apoptosis in human glioblastoma cells in vitro. The results of zymography and in vitro invasion assay showed that NF-kB inhibitors (steroid, aspirin and pentoxyfiline) suppressed the expression of uPA and invasiveness of human glioblastoma cells in vitro. This effect was accelerated by BB-94, gelatinase inhibitor. Combined with NF-kB inhibitors and recombinant human TNF-alpha, the invasive potential of human glioblastoma cells decreased and induced apoptosis in glioblastoma cells. Our results suggest that the constitutive activation of NF-κB subunits in malignant astrocytoma is realistic traget for malignant astrocytomas therapy modifying the serine and matrix metalloproteinase activities.

Research Products

• [Publications] Masaaki Yamamoto: "Correlation of the expression of nuclear factor -κB, tumor necrosis factor receptor type 1 and c-Myc with clinical course in the treatment of malignant astrocytoma"Anticancer Research. 20. 611-618 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Shuji Hagashi,Masauki Yamamoto: "Expression of nuclear factor-κB, tumor necrosis, factor receptor type 1 and c-Myc in human astrocytoma."Neurologia medico-chirurgica (Tokyo). (発表予定).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Masaaki Yamamoto, Takeo Fukushima, Shuji Hayashi Kohichi Ikeda, Hitoshi Tsugu, Hideo Kimura, Gen-Ichiro Soma, Masamichi Tomonaga: "Correlation of the expression of nuclear factor kappa B, tumor necrosis factor receptor type 1 (TNFR1) and c-Myc with the clinical course in the treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factoralpha (TNF-SAM2)"Anticancer Research. 20. 611-618 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Shuji Hayashi, Masaaki Yamamoto, Yushi Ueno, Kohichi Ikeda, Kohichi Oshima, Gen-Ichiro Soma, Takeo Fukushima: "Expression of nuclear factor-kappa B, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas."Neurologia medico-chirurgic (Tokyo). (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Masaaki Yamainoto: "Correlation of the expression of nuclear factor-κB, tumor necrosis factor receptor type I (TNFRI) and c-Myc with the clinical course in the treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2)"Auticancer Rcsearch. 20. 611-618 (2000)
• [Publications] Shuji Hayashi Masaaki Yamamoto: "Expression of nuclear factor-κB, tumor mecrosis factor receptor type 1, and c-Myc in human astrocytomas"Neurologia medico-chirungica (Tokyo). (発表予定).
• [Publications] Masaaki Yamamoto: "Correlation of the expression of nuclar tictor-KB,tumor necrosis foction reception types 1(TNFR1) and C-Mye with the treatment of recomlinent TNF-d"Anticancer Besearch. (発表予定).