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A naturally derived small molecule disrupts ligand-dependent and ligand-independent androgen receptor signaling in human prostate cancer cells.

ABSTRACT: 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.

SUBMITTER: Amin KS

PROVIDER: S-EPMC3945679 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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A naturally derived small molecule disrupts ligand-dependent and ligand-independent androgen receptor signaling in human prostate cancer cells.

Amin Karishma S KS Jagadeesh Shankar S Baishya Gakul G Rao Paruchuri G PG Barua Nabin C NC Bhattacharya Samir S Banerjee Partha P PP

Molecular cancer therapeutics 20131120 2

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 trans ...[more]

PMID: 24258347

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Project description:Prostate cancer (PCa) is a heterogeneous disease and ranked as the second leading cause of cancer-related deaths in males worldwide. The global burden of PCa keeps rising regardless of the emerging cutting-edge technologies for treatment and drug designation. There are a number of treatment options which are effectively treating localised and androgen-dependent PCa (ADPC) through hormonal and surgery treatments. However, over time, these cancerous cells progress to androgen-independent PCa (AIPC) which continuously grow despite hormone depletion. At this particular stage, androgen depletion therapy (ADT) is no longer effective as these cancerous cells are rendered hormone-insensitive and capable of growing in the absence of androgen. AIPC is a lethal type of disease which leads to poor prognosis and is a major contributor to PCa death rates. A natural product-derived compound, curcumin has been identified as a pleiotropic compound which capable of influencing and modulating a diverse range of molecular targets and signalling pathways in order to exhibit its medicinal properties. Due to such multi-targeted behaviour, its benefits are paramount in combating a wide range of diseases including inflammation and cancer disease. Curcumin exhibits anti-cancer properties by suppressing cancer cells growth and survival, inflammation, invasion, cell proliferation as well as possesses the ability to induce apoptosis in malignant cells. In this review, we investigate the mechanism of curcumin by modulating multiple signalling pathways such as androgen receptor (AR) signalling, activating protein-1 (AP-1), phosphatidylinositol 3-kinases/the serine/threonine kinase (PI3K/Akt/mTOR), wingless (Wnt)/ß-catenin signalling, and molecular targets including nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2) and cyclin D1 which are implicated in the development and progression of both types of PCa, ADPC and AIPC. In addition, the role of microRNAs and clinical trials on the anti-cancer effects of curcumin in PCa patients were also reviewed.

Project description:BACKGROUND: Prostate cancer is one of the leading causes of cancer death in men. Androgen ablation, the most commonly-used therapy for progressive prostate cancer, is ineffective once the cancer cells become androgen-independent. The regulatory mechanisms that cause this transition (from androgen-dependent to androgen-independent) remain unknown. In this study, based on the microarray data comparing global gene expression patterns in the prostate tissue between androgen-dependent and -independent prostate cancer patients, we identify a set of transcription factors and microRNAs that potentially cause such difference, using a model-based computational approach. RESULTS: From 335 position weight matrices in the TRANSFAC database and 564 microRNAs in the microRNA registry, our model identify 5 transcription factors and 7 microRNAs to be potentially responsible for the level of androgen dependency. Of these transcription factors and microRNAs, the estimated function of all the 5 transcription factors are predicted to be inhibiting transcription in androgen-independent samples comparing with the dependent ones. Six out of 7 microRNAs, however, demonstrated stimulatory effects. We also find that the expression levels of three predicted transcription factors, including AP-1, STAT3 (signal transducers and activators of transcription 3), and DBP (albumin D-box) are significantly different between androgen-dependent and -independent patients. In addition, microRNA microarray data from other studies confirm that several predicted microRNAs, including miR-21, miR-135a, and miR-135b, demonstrate differential expression in prostate cancer cells, comparing with normal tissues. CONCLUSION: We present a model-based computational approach to identify transcription factors and microRNAs influencing the progression of androgen-dependent prostate cancer to androgen-independent prostate cancer. This result suggests that the capability of transcription factors to initiate transcription and microRNAs to facilitate mRNA degradation are both decreased in androgen-independent prostate cancer. The proposed model-based approach indicates that considering combinatorial effects of transcription factors and microRNAs in a unified model provides additional transcriptional and post-transcriptional regulatory mechanisms on global gene expression in the prostate cancer with different hormone-dependency.

Dataset Information

A naturally derived small molecule disrupts ligand-dependent and ligand-independent androgen receptor signaling in human prostate cancer cells.

Publications

A naturally derived small molecule disrupts ligand-dependent and ligand-independent androgen receptor signaling in human prostate cancer cells.

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