Prostate cancer cells tolerate a narrow range of androgen receptor expression and activity.
BACKGROUND
The precise role of androgen receptor (AR) in the normal development of prostate and the progression of prostate cancer (CaP) remains controversial. While AR expression and activity is associated with growth arrest and differentiation of normal prostate cells, it is maintained in CaP cells that are characterized by continued proliferation. Our objective was to determine the importance of AR signaling for survival and growth of CaP cells, particularly those with a hormone-refractory phenotype.


METHODS
AR expression was modulated in androgen-sensitive (AS) and androgen-insensitive (AI) CaP cells using RNAi and cDNA transduction. Resulting changes in AR transcriptional activity and cell growth were quantified.


RESULTS
Interference with AR expression in both AS and AI CaP cells by shRNA transduction demonstrated a direct correlation between residual AR expression and cell viability. CaP cells lacking AR expression undergo apoptosis several days after AR down-regulation. This delayed response suggests that AR regulates apoptosis likely through an indirect mechanism. Overexpression of AR or hyper-stimulation of AR with high levels of androgen was also poorly tolerated by CaP cells. Cells with elevated AR had a growth disadvantage due to G1 cell cycle arrest and induction of p21 and GADD45 expression.


CONCLUSIONS
CaP cells expressing endogenous AR are sensitive to both increases and decreases in AR expression levels and activity. AR in CaP cells is delicately regulated to provide a balance between cell death and continued proliferation. Thus, both approaches, inhibition and over-stimulation of AR activity, may have therapeutic value for treatment of prostate cancer.
Tararova
Natalia D
ND
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Narizhneva
Natalya
N
Krivokrisenko
Vadim
V
Gudkov
Andrei V
AV
Gurova
Katerina V
KV
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
C410798:AR protein, human; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D013196:Dihydrotestosterone