Tumor suppressor function of androgen receptor coactivator ARA70alpha in prostate cancer.
Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70alpha is AR-dependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70alpha, facilitating the growth of LNCaP cells. The tumor suppressor function of ARA70alpha is consistent with our previous findings that ARA70alpha expression is decreased in prostate cancer cells compared with benign prostate. ARA70alpha also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70alpha functions as a tumor suppressor gene.
Ligr
Martin
M
Department of Pathology and Urology, New York University School of Medicine, New York Harbor Healthcare System, New York, NY 10010, USA.
Li
Yirong
Y
Zou
Xuanyi
X
Daniels
Garrett
G
Melamed
Jonathan
J
Peng
Yi
Y
Wang
Wei
W
Wang
Jinhua
J
Ostrer
Harry
H
Pagano
Michele
M
Wang
Zhengxin
Z
Garabedian
Michael J
MJ
Lee
Peng
P
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D056918:Nuclear Receptor Coactivators / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020033:Protein Isoforms; D034622:RNA Interference
C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D020033:Protein Isoforms