Abstract 266: Disulfiram overcomes docetaxel resistance in prostate cancer by targeting the neddylation pathway and down-regulation of Skp2 expression

Abstract Disulfiram (DSF), an inhibitor of aldehyde dehydrogenase and a dithiocarbamate chelator of copper, has been clinically used for treatment of alcohol dependence for decades. A population-based case control study has suggested that the use of DSF is associated with reduced risk of prostate cancer. In addition, copper is accumulated in prostate cancer and can act synergistically with DSF to inhibit the growth of prostate cancer cells. These accumulating data suggested that DSF is a very promising agent to be repurposed for prostate cancer treatment and prevention. However, the anti-cancer mechanisms of DSF currently remain largely unknown. Here we have shown that DSF treatment decreases the neddylation levels of NEDD8-conjugating enzyme UBE2M and Cullin-1 leading to down-regulation of Skp2 expression in prostate cancer DU145 cells. Further co-immunoprecipitation experiment revealed that DSF disrupted the formation of the defective in Cul neddylation 1 protein (DCN1) and UBE2M complex. DSF synergistically enhanced the growth inhibitory effect of docetaxel on prostate cancer cell lines and overcame the drug resistance. Taken together, these data may provide proof of concept for rationally designed repurpose of DSF to treat docetaxel-resistant prostate cancer by involvement of the neddylation pathway. Citation Format: Liankun Song, Bin Yu, Hong-Min Liu, Xiaolin Zi. Disulfiram overcomes docetaxel resistance in prostate cancer by targeting the neddylation pathway and down-regulation of Skp2 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 266.