Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma.
Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma.
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发表时间：
2001-05
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通讯作者：
J. Sunwoo;Zhong Chen;G. Dong;N. Yeh;C. Bancroft;E. Sausville;J. Adams;P. Elliott;C. Waes
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作者：
J. Sunwoo;Zhong Chen;G. Dong;N. Yeh;C. Bancroft;E. Sausville;J. Adams;P. Elliott;C. Waes
我们已经证明，核因子 kappa B (NF-kappa B) 的激活可促进细胞存活和生长调节癌基因 α 等细胞因子的表达，这些细胞因子可以调节鳞状细胞癌 (SCC) 的血管生成、生长和转移。癌症中 NF-kappa B 和细胞保护基因的激活可能是由信号诱导的磷酸化和抑制剂 kappa B 的蛋白酶体依赖性降解引起的。在本研究中，我们研究了新型蛋白酶体抑制剂 PS-341 对 NF-kappa B 激活以及小鼠和人类 SCC 细胞系中细胞存活、生长和血管生成的影响。 PS-341 在 10(-8) 和 10(-7) M 浓度之间抑制 NF-kappa B DNA 结合的激活和功能性报告基因活性。在 10(-7) M 浓度下，在 4 个小鼠和 2 个人类 SCC 系中观察到细胞毒性，并伴随聚 (ADP-核糖) 聚合酶（半胱天冬酶介导的细胞凋亡的标志物）的早期裂解。在体内，PS-341 以 1--2 mg/kg 的剂量（每周 3 次）抑制小鼠和人类鳞状细胞癌的生长，并且在 2 mg/kg 的剂量下出现剂量限制性毒性。肿瘤生长抑制与血管密度显着降低相关。 PS-341 在 PS-341 抑制 NF-κ B 的范围内抑制 SCC 的促血管生成细胞因子生长调节癌基因 α 和血管内皮生长因子的表达。我们得出结论，PS-341 抑制与 SCC 中细胞存活、肿瘤生长和血管生成相关的 NF-κ B 途径成分的激活。
We have shown that activation of nuclear factor-kappa B (NF-kappa B) promotes cell survival and expression of cytokines such as growth-regulated oncogene-alpha, which can modulate angiogenesis, growth, and metastasis of squamous cell carcinoma (SCC). Activation of NF-kappa B and cytoprotective genes in cancer may result from signal-induced phosphorylation and proteasome-dependent degradation of inhibitor-kappa B. In this study, we examined the effects of the novel proteasome inhibitor PS-341 on activation of NF-kappa B and cell survival, growth, and angiogenesis in murine and human SCC cell lines. PS-341 inhibited activation of NF-kappa B DNA binding and functional reporter activity at concentrations between 10(-8) and 10(-7) M. Cytotoxicity was observed at 10(-7) M in four murine and two human SCC lines, and followed early cleavage of poly(ADP-ribose) polymerase, a marker of caspase-mediated apoptosis. In vivo, PS-341 inhibited growth of murine and human SCC in mice at doses of 1--2 mg/kg given three times weekly, and dose-limiting toxicity was encountered at 2 mg/kg. Tumor growth inhibition was associated with a marked decrease in vessel density. PS-341 inhibited expression of the proangiogenic cytokines growth-regulated oncogene-alpha and vascular endothelial growth factor by SCC in the range at which PS-341 inhibits NF-kappa B. We conclude that PS-341 inhibits activation of NF-kappa B pathway components related to cell survival, tumor growth, and angiogenesis in SCC.