Cryptotanshinone down-regulates androgen receptor signaling by modulating lysine-specific demethylase 1 function
Ching-Yuan Wu1, Chang-Yi Hsieh, Ko-En Huang
1Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
International Journal of Cancer
|November 5, 2011
Summary
Cryptotanshinone inhibits prostate cancer growth by targeting androgen receptor (AR) signaling. It disrupts the AR-LSD1 interaction, reducing AR transcriptional activity and offering a potential new therapy for hormone-refractory prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer progression is linked to androgen receptor (AR) signaling.
- Hormone-refractory prostate cancer necessitates novel therapeutic strategies targeting AR signaling.
- Cryptotanshinone shows potential in inhibiting AR-positive prostate cancer cell growth.
Purpose of the Study:
- To investigate the mechanism by which cryptotanshinone inhibits AR-positive prostate cancer cell growth.
- To elucidate the molecular targets and pathways affected by cryptotanshinone.
- To evaluate cryptotanshinone as a potential therapeutic agent for prostate cancer.
Main Methods:
- Cell viability assays to assess cryptotanshinone's effect on cancer cell growth.
- Western blotting and qRT-PCR to analyze AR target gene expression.
- Co-immunoprecipitation to study AR and LSD1 interaction.
- Chromatin immunoprecipitation to examine histone modifications.
Main Results:
- Cryptotanshinone significantly inhibited the growth of AR-positive prostate cancer cells.
- Cryptotanshinone suppressed AR transcriptional activity and the expression of AR target genes.
- Cryptotanshinone disrupted the AR-LSD1 interaction, inhibiting LSD1-mediated H3K9 demethylation.
- Cryptotanshinone increased repressive histone marks (H3K9 methylation) without affecting AR protein levels or localization.
Conclusions:
- Cryptotanshinone exerts its anti-cancer effects by inhibiting AR signaling through functional inactivation of LSD1.
- This novel mechanism involves the repression of AR-dependent transcription via modulation of H3K9 methylation.
- Cryptotanshinone represents a promising therapeutic candidate for prostate cancer, particularly hormone-refractory types.
Related Concept Videos
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:22Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
01:31Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
01:26Testosterone: Functions and Regulation
The intricate hormonal interplay essential for male reproductive health begins with the release of gonadotropin-releasing hormone (GnRH) by the hypothalamus. This hormone prompts the pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH targets the Leydig cells in the testes, stimulating them to produce and release testosterone. In concert with testosterone, FSH acts on the Sertoli cells within the seminiferous tubules to facilitate the release of...