Sensitization of radio-resistant prostate cancer cells with a unique cytolethal distending toxin
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Chih-Ho Lai1,2, Chia-Shuo Chang2, Hsin-Ho Liu1, Yuh-Shyan Tsai1,3, Feng-Ming Hsu4,5, Yung-Luen Yu6, Cheng-Kuo Lai1,2, Leah Gandee1, Rey-Chen Pong1, Heng-Wei Hsu1, Lan Yu5, Debabrata Saha5 and Jer-Tsong Hsieh1,6
1 Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
2 School of Medicine, China Medical University, Taichung, Taiwan
3 Department of Urology, Medical College and Hospital, National Cheng Kung University, Tainan, Taiwan
4 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
5 Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
6 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
Chih-Ho Lai, email:
Jer-Tsong Hsieh, email:
Keywords: prostate cancer, ionizing radiation, radio-resistance, cytolethal distending toxin
Received: March 17, 2014 Accepted: June 24, 2014 Published: June 26, 2014
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces cell-cycle arrest and apoptosis in mammalian cells. Recent studies have demonstrated that prostate cancer (PCa) cells can acquire radio-resistance when DOC-2/DAB2 interactive protein (DAB2IP) is downregulated. In this study, we showed that CDT could induce cell death in DAB2IP-deficient PCa cells. A combination of CDT and radiotherapy significantly elicited cell death in DAB2IP-deficient PCa cells by inhibiting the repair of ionizing radiation (IR)-induced DNA double-strand break (DSB) during G2/M arrest, which is triggered by ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses. We also found that CDT administration significantly increased the efficacy of radiotherapy in a xenograft mouse model. These results indicate that CDT can be a potent therapeutic agent for radio-resistant PCa.
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