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Relationship of Drug Sensitivity and Expression of hypoxia-inducible factor-1 (HIF-1)

药物敏感性与缺氧诱导因子1（HIF-1）表达的关系

基本信息

批准号：
13671044
负责人：
HASHINO Satoshi
金额：
$ 1.98万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671044/
关键词：
Taxol apoptosis MyD88 NF-κB TNF-α signal transduction taxol apoptosis TNF-α signal transduction toll-like receptor 低酸素抗癌剤耐性 HIF-1 pim-1

项目摘要

We have studied the sensitivity of several leukemia cell lines to anti-cancer drugs. We have noticed that some myelomonocytic leukemia cell lines are sensitive to low concentrations of Taxol. Myelomonocytic leukemia cell lines are more sensitive to Taxol than ovary cancer cell lines. We have examined the mechanisms how myelomonocytic leukemia cell lines are sensitive to low doses of Taxol. According to the previous reports demonstrating that Taxol transduced the signal through the activation of MyD88 and NF-κB and then induced the expression of TNF-α mRNA in murine macrophages and that Taxol induced the expression of TNF-α mRNA in human cancer cells through the activation of NF-κB, we hypothesized that Taxol also transduced the signals through the activation of MyD88 in human macrophages. We first examined the activation of NF-κB and the expression of TNFα mRNA after incubaing human myelomonocytic leukemia cell lines with 10 nM Taxol. We found that Taxol induced the activation of NF-κB and the expression of TNF-α mRNA in human myelomonocytic leukemia cell lines at 10 nM. Then we next established the cell lines transfected with dominant negative MyD88 (dnMyD88). In the dnMyD88-transfectants, taxol did not induce the activation of NF-κB or the expression of TNF-αRNA. In those cells, we examined the induction of apoptosis after treatment with 10 nM Taxol. Taxol induced apoptosis in about 50 % of the vector-control cells and in 20-30 % of the dnMyD88-transfectants. These results suggest that Taxol-induced apoptosis was transduced through the activation of MyD88 and that Taxol may be useful for the treatment with myelomonocytic leukemia.

我们研究了几种白血病细胞系对抗癌药物的敏感性。我们已经注意到一些粒-单核细胞白血病细胞系对低浓度紫杉醇敏感。单核细胞白血病细胞系对紫杉醇的敏感性高于卵巢癌细胞系。我们研究了骨髓单核细胞白血病细胞系对低剂量紫杉醇敏感的机制。根据以往的报道，紫杉醇通过激活MyD88和NF-κB转导信号，进而诱导小鼠巨噬细胞表达肿瘤坏死因子-α，以及紫杉醇通过激活核因子-αB诱导人癌细胞表达肿瘤坏死因子-κ，我们推测紫杉醇也通过激活MyD88在人巨噬细胞中转导信号。我们首先检测了10 NM紫杉醇作用于人粒-单核细胞白血病细胞系后，核因子-κB的活化和α基因的表达。我们发现紫杉醇在10 nM时可诱导人单核细胞白血病细胞株中核因子κB的活化和α基因的表达。然后，我们建立了显性阴性MyD88(DnMyD88)细胞系。在dnMyD88转染体中，紫杉醇不能诱导NF-κB的活化和α的表达。在这些细胞中，我们检测了10 NM紫杉醇处理后对细胞凋亡的诱导作用。紫杉醇诱导约50%的载体对照细胞和20%-30%的dnMyD88转染体细胞发生凋亡。这些结果表明，紫杉醇诱导的细胞凋亡是通过激活MyD88来实现的，紫杉醇可能用于治疗粒-单核细胞白血病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

J.Wang, S.Hashino, et al.: "MyD88 is involved in the signalling pathway for Taxol-induced apoptosis and TNF-α expression in human myelomonocytic cells"British Journal of Haematology. 118. 638-645 (2002)

J.Wang、S.Hashino 等人：“MyD88 参与人骨髓单核细胞中紫杉醇诱导的细胞凋亡和 TNF-α 表达的信号传导途径”British Journal of Haematology 118. 638-645 (2002)。

DOI：
发表时间：
期刊：
影响因子：
0
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通讯作者：

Akakura N.: "Constitutive expression of hypoxia-inducible factor-1α (HIF-1α) renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation"Cancer Res.. 61. 6548-6554 (2001)

Akakura N.：“缺氧诱导因子 1α (HIF-1α) 的组成型表达使胰腺癌细胞对缺氧和营养剥夺诱导的细胞凋亡具有抵抗力”Cancer Res.. 61. 6548-6554 (2001)

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Wang J, Kobayashi M. Han M, Choi S, Takano M, Hashino S. Tanaka J, Kondoh T, Kawamura K, Hosokawa M.: "MyD88 is involved in signaling pathway for Taxol-induced apoptosis and TNF-・ expression in human myelomonocytic cells"Br J. Haematol.. 118. 638-645 (200

Wang J、Kobayashi M. Han M、Choi S、Takano M、Hashino S. Tanaka J、Kondoh T、Kawamura K、Hosokawa M.：“MyD88 参与人骨髓单核细胞中紫杉醇诱导的细胞凋亡和 TNF 表达的信号通路细胞“Br J. Haematol.. 118. 638-645 (200