Abstract
Carbidopa, a peripheral decarboxylase inhibitor used with L-DOPA to treat Parkinson’s disease, has attracted significant interest in recent years for its anticancer effect. Increasing evidence reveals that Carbidopa can inhibit cancer cell growth and induce apoptosis through aryl hydrocarbon receptor (AHR) in some cancers. However, the antitumor effect 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 of PCa by downregulating the protein expression of AR. Carbidopa inhibits proliferation and migration of LNCaP cells and promotes apoptosis, but has no effect on the AR-independent prostate cell line DU145. Carbidopa increases ubiquitination of AR in LNCaP cells. Several studies have shown that AHR can act as an E3 ubiquitin ligase and promote the proteasomal degradation of AR. Quantitative RT-PCR, immunofluorescence staining and immunoblotting assay demonstrate that AHR is induced and activated by Carbidopa, and the co-immunoprecipitation assay shows that AR interacts with AHR, firmly confirming that Carbidopa decreases AR protein level though AHR-induced proteasomal degradation. In addition, Carbidopa suppresses PCa growth in vivo when xenografted into immunocompromised mice. Carbidopa treatment increases AHR protein level and decreases AR protein level in tumor tissues. Taken together, our study implicates Carbidopa for the first time in effective suppression of prostate cancer via a mechanism, involving AHR-mediated proteasomal degradation of AR.
Highlights
Prostate cancer (PCa) is one of the most prevalent cancers in males[1]
In order to determine whether Carbidopa can inhibit PCa growth, we used four human PCa cell lines in our study: LNCaP, VCAP, PC3, and DU145
To determine the effect of Carbidopa on cell apoptosis, LNCaP, VCAP, PC3, and DU145 cells were treated with increasing doses of Carbidopa (10, 50, and 100 μM) for 24 h, and cells were analyzed by flow cytometry
Summary
The growth of prostate tumors is dependent on androgens that activate the androgen receptor (AR) in tumor cells, and promote their survival and proliferation[2]. AR plays a key role in the development of PCa. Androgen deprivation therapy (ADT), the first-line treatment for metastatic PCa, primarily acts to reduce gonadal androgens through chemical or surgical castration, and/or disrupts AR signaling with the use of antiandrogens, such as bicalutamide[3]. Most PCas transform into castrationresistant PCa (CRPC) after ADT and lead to cancer recurrence, and AR is re-expressed and functions during this progression[4]. Despite the lack of dependence of CRPC on androgens, it is widely accepted that AR signaling still drives tumor growth[5]. Downregulation of AR can still be an effective means of treating
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