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J. Microbiol. Biotechnol. 2008; 18(3): 523-531

Published online March 28, 2008

Copyright © The Korean Society for Microbiology and Biotechnology.

Sensitization of the Apoptotic Effect of γ-Irradiation in Genistein-pretreated CaSki Cervical Cancer Cells

Shin, Jang-In , Jung-Hyun Shim , Ki-Hong Kim , Hee-Sook Choi , Jae-Wha Kim 1, Hee- Gu Lee 1, Bo-Yeon Kim 1, Sue-Nie Park 2, Ok-Jin Park 3 and Do-Young Yoon 3*

Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Korea, 1Cellomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-600, Korea, 2Division of Genetic Toxicology, National Institute of Toxicological Research, Seoul 122-704, Korea, 3Department of Nutrition, Hannam University, Daejeon 305-764, Korea

Abstract

Radiotherapy is currently applied in the treatment of human cancers. We studied whether genistein would enhance the radiosensitivity and explored its precise molecular mechanism in cervical cancer cells. After co-treatment with genistein and irradiation, the viability, cell cycle analysis, and apoptosis signaling cascades were elucidated in CaSki cells. The viability was decreased by co-treatment with genistein and irradiation compared with irradiation treatment alone. Treatment with only ${\gamma}$-irradiation led to cell cycle arrest at the $G_1$ phase. On the other hand, co-treatment with genistein and ${\gamma}$-irradiation caused a decrease in the $G_1$ phase and a concomitant increase up to 56% in the number of $G_2$ phase. In addition, co-treatment increased the expression of p53 and p21, and Cdc2-tyr-15-p, supporting the occurrence of $G_2/M$ arrest. In general, apoptosis signaling cascades were activated by the following events: release of cytochrome c, upregulation of Bax, down regulation of Bcl-2, and activation of caspase-3 and -8 in the treatment of genistein and irradiation. Apparently, co-treatment downregulated the transcripts of E6*I, E6*II, and E7. Genistein also stimulated irradiation-induced intracellular reactive oxygene, species (ROS) production, and co-treatment-induced apoptosis was inhibited by the antioxidant N-acetylcysteine, suggesting that apoptosis has occurred through the increase in ROS by genistein and ${\gamma}$-irradiation in cervical cancer cells. Gamma-irradiation increased cyclooxygenase-1 (COX-2) expression, whereas the combination with genistein and ${\gamma}$-irradiation almost completely prevented irradiation-induced COX-2 expression and $PGE_2$ production. Co-treatment with genistein and ${\gamma}$-irradiation inhibited proliferation through $G_2/M$ arrest and induced apoptosis via ROS modulation in the CaSki cancer cells.

Keywords: Genistein, CaSki cervical, cancer cells, apoptosis, γ-irradiation, ROS