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.

中文翻译：

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卡比多巴通过芳烃受体介导的泛素化和雄激素受体的降解来抑制前列腺癌。

卡比多巴是一种与L-DOPA一起用于治疗帕金森氏病的外周脱羧酶抑制剂，近年来因其抗癌作用而引起了广泛的关注。越来越多的证据表明，在某些癌症中，卡比多巴可以抑制癌细胞的生长并通过芳烃受体（AHR）诱导凋亡。但是，卡比多巴在前列腺癌（PCa）中的抗肿瘤作用尚未完全了解。雄激素受体（AR）在PCa中也起着核心作用，即使在晚期的“耐cast酸盐的”疾病中也是如此。在本研究中，我们报道卡比多巴通过下调AR的蛋白表达来抑制PCa的生长。卡比多巴抑制LNCaP细胞的增殖和迁移并促进细胞凋亡，但对非AR依赖的前列腺细胞DU145没有影响。卡比多巴可增加LNCaP细胞中AR的泛素化。几项研究表明，AHR可以充当E3泛素连接酶并促进AR的蛋白酶体降解。定量RT-PCR，免疫荧光染色和免疫印迹试验表明，卡比多巴诱导并激活了AHR，而共免疫沉淀试验表明，AR与AHR相互作用，从而坚定地证明了卡比多巴通过AHR诱导的蛋白酶体降解降低了AR蛋白水平。此外，当异种移植到免疫功能低下的小鼠体内时，卡比多巴抑制体​​内PCa的生长。卡比多巴治疗可增加肿瘤组织中的AHR蛋白水平并降低AR蛋白水平。两者合计，我们的研究首次涉及卡比多巴通过一种机制来有效抑制前列腺癌，该机制涉及AHR介导的AR的蛋白酶体降解。