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.
Highlights
Anti-androgen Bicalutamide Disrupts Telomeric Complexes in Prostate Cancer Cells—The disruption of telomeric complexes has been shown to elicit a DNA damage response, which leads to the recruitment of 53BP1
These observations support the possibility that androgen receptor (AR) interacts with telomeric proteins to preserve structural and/or functional stability of telomeric complexes, and agents that interfere with AR may disrupt telomeric complexes required for the viability of prostate cancer cells
The understanding that AR is indispensable for proliferation and viability of prostate cancer cells has led to the development of a myriad of therapies targeting AR for the treatment of prostate cancer
Summary
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. These studies indicate that AR is a structural component of telomeric complexes and its inhibition by Casodex disrupts telomeric complexes required for the viability of prostate cancer cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
