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.
Our findings demonstrate a molecular link between Campylobacter jejuni CDT and cholesterol, which is crucial to facilitate CDT-induced pathogenesis in hosts.
With advances in molecular biologic and genomic technology, detailed molecular mechanisms for development of castration-resistant prostate cancer (CRPC) have surfaced. Metastatic prostate cancer (PCa) no longer represents an end stage, with many emerging therapeutic agents approved as effective in prolonging survival of patients from either pre- or post-docetaxel stage. Given tumor heterogeneity in patients, a one-size-fits-all theory for curative therapy remains questionable. With the support of evidence from continuing clinical trials, each treatment modality has gradually been found suitable for selective best-fit patients: e.g., new androgen synthesis inhibitor arbiraterone, androgen receptor signaling inhibitor enzalutamide, sipuleucel-T immunotherapy, new taxane carbazitaxel, calcium-mimetic radium-223 radiopharmaceutical agent. Moreover, several emerging immunomodulating agents and circulating tumor cell enumeration and analysis showed promise in animal or early phase clinical trials. While the era of personalized therapy for CRPC patients is still in infancy, optimal therapeutic agents and their sequencing loom not far in the future.
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