Amin Karishma S, Jagadeesh Shankar, Baishya Gakul, Rao Paruchuri G, Barua Nabin C, Bhattacharya Samir, Banerjee Partha P
Corresponding Author: Partha P. Banerjee, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20057.
Mol Cancer Ther. 2014 Feb;13(2):341-52. doi: 10.1158/1535-7163.MCT-13-0478. Epub 2013 Nov 20.
Continued reliance on androgen receptor (AR) signaling is a hallmark of prostate cancer, including the development of castration-resistant prostate cancer (CRPC), making it an attractive therapeutic target for prostate cancer treatment. Mahanine is a novel carbazole alkaloid derived from the leaves of Murraya koenigii, commonly known as the curry leaf plant, which grows widely across East-Asia. We show here that mahanine possesses the ability to inhibit ligand-dependent and -independent AR transactivation, leading to a prominent decline in AR target gene expression. Mahanine treatment causes a time- and dose-dependent decline in AR protein levels, including truncated AR splice variants, in a panel of androgen-responsive and -independent prostate cancer cells. The decrease in AR levels induced by mahanine occurs posttranslationally by proteasomal degradation, without any change in the AR gene expression. Mahanine treatment induces an outward movement of the AR from the nucleus to the cytoplasm, leading to an initial increase in cytoplasmic AR levels, followed by a gradual decline in the AR levels in both cellular compartments. Ligand-induced AR phosphorylation at Ser-81, a phospho-site associated with prostate cancer cell growth and AR transactivity, is greatly diminished in the presence of mahanine. The decline in AR phosphorylation at Ser-81 by mahanine occurs via the inactivation of mitotic kinase CDK1. Collectively, our data demonstrate that mahanine strongly disrupts AR signaling and inhibits the growth of androgen-dependent and -independent prostate cancer cells, thereby implicating a therapeutic role of mahanine in prostate cancer treatment.
持续依赖雄激素受体（AR）信号传导是前列腺癌的一个标志，包括去势抵抗性前列腺癌（CRPC）的发展，这使其成为前列腺癌治疗中一个有吸引力的治疗靶点。马汉宁是一种新型咔唑生物碱，源自俗称咖喱叶植物的九里香的叶子，该植物在东亚广泛生长。我们在此表明，马汉宁具有抑制配体依赖性和非依赖性AR反式激活的能力，导致AR靶基因表达显著下降。在一组雄激素反应性和非依赖性前列腺癌细胞中，马汉宁处理导致AR蛋白水平呈时间和剂量依赖性下降，包括截短的AR剪接变体。马汉宁诱导的AR水平下降通过蛋白酶体降解在翻译后发生，而AR基因表达没有任何变化。马汉宁处理诱导AR从细胞核向细胞质的外向移动，导致细胞质AR水平最初增加，随后两个细胞区室中的AR水平逐渐下降。在存在马汉宁的情况下，配体诱导的Ser-81处的AR磷酸化（与前列腺癌细胞生长和AR反式活性相关的磷酸化位点）大大减少。马汉宁导致的Ser-81处AR磷酸化下降是通过有丝分裂激酶CDK1的失活发生的。总体而言，我们的数据表明，马汉宁强烈破坏AR信号传导并抑制雄激素依赖性和非依赖性前列腺癌细胞的生长，从而暗示马汉宁在前列腺癌治疗中的治疗作用。
