ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction.

The Journal of Biological Chemistry
Vidyavathi ReddySahn-Ho Kim

Abstract

Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of c...Continue Reading

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Citations

Jul 5, 2017·Nature Reviews. Urology·Mindy Kim Graham, Alan Meeker
Feb 10, 2019·International Journal of Cancer. Journal International Du Cancer·Vibha SinghArrigo De Benedetti
Jan 10, 2020·Current Topics in Medicinal Chemistry·Joseph BereiNeelu Puri
Nov 8, 2020·International Journal of Molecular Sciences·Antje M WengnerBernard Haendler

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