Benzyl isothiocyanate-induced DNA damage causes G2/M cell cycle arrest and apoptosis in human pancreatic cancer cells.
Benzyl isothiocyanate-induced DNA damage causes G2/M cell cycle arrest and apoptosis in human pancreatic cancer cells.
复制标题
DOI：
10.1093/jn/136.11.2728
复制
发表时间：
2006-11
期刊：
影响因子：
--
通讯作者：
Rui-Fang Zhang;Sivakumar Loganathan;I. Humphreys;S. Srivastava
中科院分区：
文献类型：
--
作者：
Rui-Fang Zhang;Sivakumar Loganathan;I. Humphreys;S. Srivastava
异硫氰酸苄酯（BITC）已被证明可以抑制实验动物中化学诱导的胰腺癌。然而，负责BITC的抗癌作用的机制尚不清楚。在这项研究中，我们测试了BITC治疗是否会影响Capan-2人胰腺癌细胞的生长。BITC（10 μ mol/L）处理引起H2A.x的显著磷酸化（2.6倍）和对Capan-2细胞的永久性损伤。BITC介导的G2/M期阻滞与细胞周期蛋白依赖性激酶抑制剂p21（Waf 1/Cip 1）的上调和检查点激酶2的激活相关，而其他G2/M期调节蛋白，包括CyclinB 1，Cdc 2和细胞分裂周期25 C（Cdc 25 C）的表达分别与对照组相比下调了19%，51%和70%。这些变化导致Cdc 2激酶活性抑制55%。此外，Cdc 25 C表达的下降被完全阻断时，细胞用lactacystin（蛋白酶体抑制剂）处理BITC治疗之前。然而，G2/M期阻滞和BITC诱导的细胞凋亡的部分阻断与lactacystin预处理细胞。综上所述，本研究的结果表明，在介导的G2/M期细胞周期阻滞和细胞凋亡的Capan-2细胞中，BITC靶向的多个信号通路的参与，并值得进一步调查。
Benzyl isothiocyanate (BITC) has been shown to inhibit chemically induced pancreatic cancer in experimental animals. However, the mechanism responsible for the anticancer effects of BITC is not clearly understood. In this study, we tested whether BITC treatment would affect the growth of Capan-2 human pancreatic cancer cells. BITC (10 micromol/L) treatment caused marked phosphorylation of H2A.x (2.6-fold) and permanent damage to Capan-2 cells. BITC-mediated G2/M arrest was associated with up-regulation of cyclin dependent kinase inhibitor p21(Waf1/Cip1) and the activation of checkpoint kinase 2, whereas the expressions of other G2/M regulatory proteins, including CyclinB1, Cdc2, and cell division cycle 25C (Cdc25C), were down-regulated by 19, 51, and 70%, respectively, compared with control. These changes resulted in a 55% inhibition of Cdc2 kinase activity. In addition, the decline in the expression of Cdc25C was completely blocked when the cells were treated with lactacystin (proteasome inhibitor) prior to BITC treatment. However, G2/M arrest and apoptosis induced by BITC were partially blocked by pretreatment of cells with lactacystin. Taken together, the results of this study suggest the involvement of multiple signaling pathways targeted by BITC in mediating G2/M cell cycle arrest and apoptosis in Capan-2 cells and warrant further investigation.