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.
Highlights
Prostate cancer (PCa) is one of the most prevalent male cancers in many western developed countries, and its incidence is increasing worldwide [1]
Considering the therapeutic potential of Cytolethal distending toxin (CDT), we aimed to evaluate whether CDT holotoxin exhibits any cytolethal activity in PCa cells
A significant cytotoxic effect of CDT treatment was observed in DAB2 interactive protein (DAB2IP)-deficient cells (Figure 1C), whereas this was not observed in control cells
Summary
Prostate cancer (PCa) is one of the most prevalent male cancers in many western developed countries, and its incidence is increasing worldwide [1]. For patients with inoperable disease or high risk of cancer recurrence, radiation therapy is considered an optimal choice [2,3]. Some of these patients present with intrinsic radio-resistance or develop radio-resistance prior to or after radiotherapy [4]. Loss of DAB2IP expression in PCa cells has been reported to provide a survival advantage and resistance to stress-induced apoptosis [8]. Reduced expression of DAB2IP in PCa cells induces epithelialmesenchymal transition (EMT), leading to cancer metastasis [9], and these cells acquire radio-resistance to ionizing radiation (IR)-induced apoptosis [10]. It is imperative to develop a strategy to overcome radioresistant phenotype of these cells in order to maximize the efficacy of radiation therapy
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