Sensitization of the apoptotic effect of gamma-irradiation in genistein-pretreated CaSki cervical cancer cells.
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 G1 phase. On the other hand, co-treatment with genistein and gamma-irradiation caused a decrease in the G1 phase and a concomitant increase up to 56% in the number of G2 phase. In addition, cotreatment increased the expression of p53 and p21, and Cdc2- tyr-15-p, supporting the occurrence of G2/M arrest. In general, apoptosis signaling cascades were activated by the following events: release of cytochrome c, upregulation of Bax, downregulation 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 PGE2 production. Co-treatment with genistein and gamma-irradiation inhibited proliferation through G2/M arrest and induced apoptosis via ROS modulation in the CaSki cancer cells.
Shin
Jang-In
JI
Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Korea.
Shim
Jung-Hyun
JH
Kim
Ki-Hong
KH
Choi
Hee-Sook
HS
Kim
Jae-Wha
JW
Lee
Hee-Gu
HG
Kim
Bo-Yeon
BY
Park
Sue-Nie
SN
Park
Ok-Jin
OJ
Yoon
Do-Young
DY
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000628:therapy*
D051017:Apoptosis Regulatory Proteins; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D019833:Genistein; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate