Niina Ichiro, Uchiumi Takeshi, Izumi Hiroto, Torigoe Takayuki, Wakasugi Tetsuro, Igarashi Tomonori, Miyamoto Naoya, Onitsuka Takamitsu, Shiota Masaki, Okayasu Ryuichi, Chijiiwa Kazuo, Kohno Kimitoshi
Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Iseigaoka, Fukuoka, Japan.
Cancer Sci. 2007 Jun;98(6):858-63. doi: 10.1111/j.1349-7006.2007.00476.x. Epub 2007 Apr 18.
Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA topoisomerase I and II inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA topoisomerase inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance.
抗癌药物对转录因子的修饰在凋亡信号和生存信号中均发挥重要作用。在此我们报告，DNA拓扑异构酶I和II抑制剂（如SN-38和依托泊苷），而非顺铂、5-氟尿嘧啶或放线菌素D，能够诱导转录因子Sp1磷酸化。此外，DNA拓扑异构酶抑制剂可反式激活依赖GC盒的启动子，如SV40和血管内皮生长因子启动子。依托泊苷处理30分钟内即可检测到Sp1的磷酸化形式，而PI3K抑制剂渥曼青霉素的存在以及DNA依赖蛋白激酶（DNA-PK）的敲低可使其大大减少。我们还证实，依托泊苷和SN-38处理均可使DNA-PK的磷酸化形式增加。综上所述，这些发现证明了抗癌药物诱导Sp1磷酸化的一种新的基因组反应，可能有助于肿瘤进展和耐药性。
