Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor

摘要

Carbidopa, a peripheral decarboxylase inhibitor used with L-DOPA to treat Parkinson’s disease, has attracted significantinterest in recent years for its anticancer effect. Increasing evidence reveals that Carbidopa can inhibit cancer cellgrowth and induce apoptosis through aryl hydrocarbon receptor (AHR) in some cancers. However, the antitumoreffect of Carbidopa in prostate cancer (PCa) is not fully understood. Androgen receptor (AR) plays a central role in PCa,even in advanced “castrate-resistant” disease. In the present study, we report that Carbidopa suppresses the growth ofPCa by downregulating the protein expression of AR. Carbidopa inhibits proliferation and migration of LNCaP cells andpromotes apoptosis, but has no effect on the AR-independent prostate cell line DU145. Carbidopa increasesubiquitination of AR in LNCaP cells. Several studies have shown that AHR can act as an E3 ubiquitin ligase andpromote the proteasomal degradation of AR. Quantitative RT-PCR, immunofluorescence staining and immunoblottingassay demonstrate that AHR is induced and activated by Carbidopa, and the co-immunoprecipitation assay shows thatAR interacts with AHR, firmly confirming that Carbidopa decreases AR protein level though AHR-induced proteasomaldegradation. In addition, Carbidopa suppresses PCa growth in vivo when xenografted into immunocompromisedmice. Carbidopa treatment increases AHR protein level and decreases AR protein level in tumor tissues. Takentogether, our study implicates Carbidopa for the first time in effective suppression of prostate cancer via a mechanism,involving AHR-mediated proteasomal degradation of AR.