Thermosensitization and induction of apoptosis or cell-cycle arrest via the MAPK cascade by parthenolide, an NF-κB inhibitor, in human prostate cancer androgen-independent cell lines
Thermosensitization and induction of apoptosis or cell-cycle arrest via the MAPK cascade by parthenolide, an NF-κB inhibitor, in human prostate cancer androgen-independent cell lines
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DOI：
10.3892/ijmm.2011.760
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发表时间：
2011-12-01
影响因子：
5.4
通讯作者：
Shioura, Hiroki
中科院分区：
文献类型：
--
作者：
Hayashi, Sachiko;Koshiba, Ken;Shioura, Hiroki
核因子-κ B（NF-κ B）抑制剂Parthenonucleotide（PTL）具有明显的热增强效应。在人前列腺癌雄激素非依赖性细胞系PC 3和DU 145中研究了在热疗之前用PTL处理对热敏性的修饰。此外，我们还通过ERK 1/2、p38和SAPK/JNK信号通路对丝裂原活化蛋白激酶（MAPK）的影响，分析了其诱导细胞凋亡或G（2）/M期阻滞的相关机制。在41.0 ℃或42.0 ℃的轻度高温在两种细胞系中引起的致命损伤导致低水平的热敏性，而与PTL的顺序组合显示出显着的热敏性。逐步高温（SUH）（42摄氏度持续30分钟，43.0摄氏度或43.5摄氏度持续不同时间）降低了细胞对第二次加热的热敏性。然而，在SUH之前给予PTL作为预处理防止了SUB诱导的热耐受性并导致显著的热敏化。PTL和44.0 ° C高温的组合诱导的细胞凋亡通过使用流式细胞术的亚G分裂细胞的比率来确定，与单一处理相比，亚G分裂细胞的比率显著增加，并且在PC 3中比在DU 145细胞中更有效。通过蛋白质印迹法检测了PTL和高温处理后MAPK级联反应中ERK 1/2、p38和SAPK/JNK信号传导的行为。对于PC 3细胞，PTL和热疗联合处理与单独处理相比，ras下游p-ERK 1/2被激活，p-p38轻微激活。对于DU 145细胞，ERK 1/2没有变化，而p38和SAPK/JNK在联合处理后略有激活。这些结果与通过MAPK级联反应诱导细胞凋亡、G（2）/M细胞周期阻滞和细胞致死性损伤的增加有关。总之，我们的研究结果表明，PTL是一种有效的热敏剂多学科治疗人类前列腺癌。
Parthenolide (PTL), a nuclear factor-kappa B (NF-kappa B) inhibitor, has a significant thermo-enhancement effect. Modification of thermosensitivity by treatment with PTL prior to hyperthermia was investigated in the human prostate cancer androgen-independent cell lines PC3 and DU145. In addition, we analyzed the mechanisms related to induction of apoptosis or G(2)/M cell-cycle arrest via the effects of ERK1/2, p38 and SAPK/JNK signaling on mitogen-activated protein kinase (MAPK). Lethal damage caused by mild hyperthermia at 41.0 degrees C or 42.0 degrees C in both cell lines resulted in a low level of thermosensitivity, while sequential combination with PTL showed significant thermosensitization. Step-up hyperthermia (SUH) (42 degrees C for 30 min, 43.0 degrees C or 43.5 degrees C for various periods) reduced the thermosensitivity of the cells to second heating. However, PTL given as pre-treatment prior to SUH prevented SUB-induced thermal tolerance and resulted in significant thermosensitization. Induction of apoptosis by the combination of PTL and hyperthermia at 44.0 degrees C was determined by the ratio of sub-G, division cells using flow cytometry, which was increased significantly in comparison with single treatment, and was more effective in PC3 than DU145 cells. The behavior of ERK1/2, p38, and SAPK/JNK signaling in the MAPK cascade by treatment with PTL and hyperthermia were examined by Western blotting. As for PC3 cells, ras-downstream p-ERK1/2 was activated and p-p38 slightly activated by combined treatment with PTL and hyperthermia in comparison with each alone. As for DU145 cells, ERK1/2 was not changed, while p38 and SAPK/JNK were slightly activated by combination treatment. These results were related to increases in the induction of apoptosis, G(2)/M cell cycle arrest, and lethal damage of cells via the MAPK cascade. Together, our findings demonstrate that PTL is an effective thermosensitizing agent for multidisciplinary therapy for human prostate cancer.