Investigation of Campylobacter Jejuni Genotoxin in Regulation of Autophagy

Cytolethal distending toxin (CDT), a genotoxin produced by Campylobacter jejuni, is composed of three subunits: CdtA, CdtB, and CdtC. Among these three proteins, CdtB is a DNase causing double-strand DNA break in the nucleus, resulting in cell cycle arrest at the G2/M stage, and apoptosis. Meanwhile, CdtA and CdtC bind to the lipid rafts on the cytoplasmic membrane, which is necessary for delivering CdtB to the cell. This study attempts to use CdtB as a therapeutic agent for killing prostate cancer (PCa) cells. Although radiation therapy is an effective modality for treatment of localized PCa, patients often develop radio-resistance after radiation therapy. Therefore, establishing a therapeutic system using CdtB will benefit the treatment of the disease. The radio-resistance as well as aggressive metastasis and increasing cancer stem cells (CSC) are associated with the loss of DOC-2/DAB2 interactive protein (DAB2IP); however, CDT can sensitize radio-resistant prostate cancer stem cells (PCSC) to radiation. It is also found that CDT prevents the formation of autophagosomes through inhibition of c-Myc expression. Accordingly, this study will (a) investigate how CDT suppresses autophagy in PCa cells and sensitizes PCa cells that are resistant to radiation, (b) use encapsulate nanoparticles with CdtB proteins that is fused with a signal that targets at PCa cells, (c) and test the efficacy of these nanoparticles in killing PCSC in mouse models. The results from this study will be useful for treating prostate cancer.

Project ID:PD10507-0131
External Project ID:MOST105-2313-B182-001