Peroxiredoxin 1 interacts with androgen receptor and enhances its transactivation.
Although hypoxia is accepted as an important microenvironmental factor influencing tumor progression and treatment response, it is usually regarded as a static global phenomenon. Consequently, less attention is given to the impact of dynamic changes in tumor oxygenation in regulating the behavior of cancer cells. Androgen receptor (AR) signaling plays a critical role in prostate cancer. We previously reported that hypoxia/reoxygenation, an in vitro condition used to mimic an unstable oxygenation climate in a tumor, stimulates AR activation. In the present study, we showed that peroxiredoxin 1 (Prx1), a member of the peroxiredoxin protein family, acts as a key mediator in this process. We found that the aggressive LN3, C4-2, and C4-2B prostate cancer cell lines derived from LNCaP possess constitutively elevated Prx1 compared with parental cells, and display greater AR activation in response to hypoxia/reoxygenation. Although the cell survival-enhancing property of Prx1 has traditionally been attributed to its antioxidant activity, the reactive oxygen species-scavenging activity of Prx1 was not essential for AR stimulation because Prx1 itself was oxidized and inactivated by hypoxia/reoxygenation. Increased AR transactivation was observed when wild-type Prx1 or mutant Prx1 (C52S) lacking antioxidant activity was introduced into LNCaP cells. Reciprocal immunoprecipitation, chromatin immunoprecipitation, and in vitro pull-down assays corroborated that Prx1 interacts with AR and enhances its transactivation. We also show that Prx1 is capable of sensitizing a ligand-stimulated AR. Based on the above information, we suggest that disrupting the interaction between Prx1 and AR may serve as a fruitful new target in the management of prostate cancer.
Park
Soo-Yeon
SY
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Yu
Xiaofei
X
Ip
Clement
C
Mohler
James L
JL
Bogner
Paul N
PN
Park
Young-Mee
YM
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D010100:Oxygen / Q000378:metabolism; D010544:Peroxidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection
D011944:Receptors, Androgen; D010544:Peroxidases; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D017430:Prostate-Specific Antigen; D010100:Oxygen