Abstract
The telomeric complex, shelterin, plays a critical role in protecting chromosome ends from erosion, and disruption of these complexes can lead to chromosomal instability culminating in cell death or malignant transformation. We reported previously that dominant-negative mutants of one of the telomeric proteins called TIN2 cause death of androgen receptor (AR)-negative but not AR-positive prostate cancer cells, raising the question of a possible role of AR in the structural stability of telomeric complexes. Consistent with this possibility, in the present study, we observed that the AR antagonist Casodex (bicalutamide) disrupted telomeric complexes in AR-positive LNCaP cells but not in AR-negative PC-3 cells. Immunofluorescent studies revealed colocalization of TIN2 and AR. Reciprocal immunoprecipitation studies showed association of AR with telomeric proteins. Furthermore, telomeric proteins were overexpressed in prostate cancer cells compared with normal prostate epithelial cells, and sucrose density gradient analysis showed co-sedimentation of AR with telomeric proteins in a shelterin-like mega complex. Together, these observations suggest an allosteric role of AR in telomere complex stability in prostate cancer cells and suggest that AR-antagonist Casodex-mediated cell death may be due to telomere complex disruption.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgen Antagonists / pharmacology
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Anilides / pharmacology
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA Damage / drug effects
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Fluorescent Antibody Technique
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Gene Expression Regulation, Neoplastic
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Nitriles / pharmacology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Shelterin Complex
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Telomere / genetics
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Telomere / metabolism*
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Telomere-Binding Proteins / genetics
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Telomere-Binding Proteins / metabolism*
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Telomeric Repeat Binding Protein 1 / genetics
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Telomeric Repeat Binding Protein 1 / metabolism
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Telomeric Repeat Binding Protein 2 / genetics
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Telomeric Repeat Binding Protein 2 / metabolism
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Tosyl Compounds / pharmacology
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Tumor Cells, Cultured
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Tumor Suppressor p53-Binding Protein 1
Substances
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AR protein, human
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Androgen Antagonists
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Anilides
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Intracellular Signaling Peptides and Proteins
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Nitriles
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RNA, Messenger
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Receptors, Androgen
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Shelterin Complex
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TERF2 protein, human
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TINF2 protein, human
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TP53BP1 protein, human
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Telomere-Binding Proteins
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Telomeric Repeat Binding Protein 1
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Telomeric Repeat Binding Protein 2
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Tosyl Compounds
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Tumor Suppressor p53-Binding Protein 1
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bicalutamide