Telomerase as an important target of androgen signaling blockade for prostate cancer treatment.
As the mainstay treatment for advanced prostate cancer, androgen deprivation therapy (ADT) targets the action of androgen receptor (AR) by reducing androgen level and/or by using anti-androgen to compete with androgens for binding to AR. Albeit effective in extending survival, ADT is associated with dose-limiting toxicity and the development of castration-resistant prostate cancer (CRPC) after prolonged use. Because CRPC is lethal and incurable, developing effective strategies to enhance the efficacy of ADT and circumvent resistance becomes an urgent task. Continuous AR signaling constitutes one major mechanism underlying the development of CRPC. The present study showed that methylseleninic acid (MSA), an agent that effectively reduces AR abundance, could enhance the cancer-killing efficacy of the anti-androgen bicalutamide in androgen-dependent and CRPC cells. We found that the combination of MSA and bicalutamide produced a robust downregulation of prostate-specific antigen and a recently identified AR target, telomerase, and its catalytic subunit, human telomerase reverse transcriptase. The downregulation of hTERT occurs mainly at the transcriptional level, and reduced AR occupancy of the promoter contributes to downregulation. Furthermore, apoptosis induction by the two agents is significantly mitigated by the restoration of hTERT. Our findings thus indicate that MSA in combination with anti-androgen could represent a viable approach to improve the therapeutic outcome of ADT. Given the critical role of hTERT/telomerase downregulation in mediating the combination effect and the fact that hTERT/telomerase could be measured in blood and urine, hTERT/telomerase could serve as an ideal tumor-specific biomarker to monitor the efficacy of the combination therapy noninvasively.
Liu
Shuang
S
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA.
Qi
Yanfeng
Y
Ge
Yubin
Y
Duplessis
Tamika
T
Rowan
Brian G
BG
Ip
Clement
C
Cheng
Helen
H
Rennie
Paul S
PS
Horikawa
Izumi
I
Lustig
Arthur J
AJ
Yu
Qun
Q
Zhang
Haitao
H
Dong
Yan
Y
D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D034622:RNA Interference; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology*
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D009570:Nitriles; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C008493:methylselenic acid; C053541:bicalutamide; C509186:TERT protein, human; D019098:Telomerase; D017430:Prostate-Specific Antigen