IngentaConnect DNA topoisomerase inhibitor, etoposide, enhances GC-box-dependent...

Authors: Niina, Ichiro; Uchiumi, Takeshi¹; Izumi, Hiroto¹; Torigoe, Takayuki¹; Wakasugi, Tetsuro¹; Igarashi, Tomonori¹; Miyamoto, Naoya¹; Onitsuka, Takamitsu¹; Shiota, Masaki¹; Okayasu, Ryuichi²; Chijiiwa, Kazuo³; Kohno, Kimitoshi

Source: Cancer Science, Volume 98, Number 6, June 2007 , pp. 858-863(6)

Publisher: Blackwell Publishing

Abstract:

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. (Cancer Sci 2007; 98: 858-863)

Document Type: Research article

DOI: 10.1111/j.1349-7006.2007.00476.x

Affiliations: 1: Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Kitakyushu, Fukuoka 807-8555; 2: International Space Radiation Laboratory, National Institute of Radiological Science, 4-9-1 Anagawa, Inage-ku, Chiba-shi 263-8555; 3: Department of Surgical Oncology and Regulation of Organ Function, School of Medicine, Miyazaki University, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan

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DNA topoisomerase inhibitor, etoposide, enhances GC-box-dependent promoter activity via Sp1 phosphorylation