Sensitization of radio-resistant prostate cancer cells with a unique cytolethal distending toxin

Abstract

// Chih-Ho Lai 1,2 , Chia-Shuo Chang 2 , Hsin-Ho Liu 1 , Yuh-Shyan Tsai 1,3 , Feng-Ming Hsu 4,5 , Yung-Luen Yu 6 , Cheng-Kuo Lai 1,2 , Leah Gandee 1 , Rey-Chen Pong 1 , Heng-Wei Hsu 1 , Lan Yu 5 , Debabrata Saha 5 and Jer-Tsong Hsieh 1,6 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 Correspondence: 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 Abstract 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.