Phosphorylation and activation of androgen receptor by Aurora-A.
Aurora-A kinase is frequently overexpressed/activated in various types of human malignancy, including prostate cancer. In this study, we demonstrate elevated levels of Aurora-A in androgen-refractory LNCaP-RF but not androgen-sensitive LNCaP cells, which prompted us to examine whether Aurora-A regulates the androgen receptor (AR) and whether elevated Aurora-A is involved in androgen-independent cell growth. We show that ectopic expression of Aurora-A induces AR transactivation activity in the presence and absence of androgen. Aurora-A interacts with AR and phosphorylates AR at Thr(282) and Ser(293) in vitro and in vivo. Aurora-A induces AR transactivation activity in a phosphorylation-dependent manner. Ectopic expression of Aurora-A in LNCaP cells induces prostate-specific antigen expression and cell survival, whereas knockdown of Aurora-A sensitizes LNCaP-RF cells to apoptosis and cell growth arrest. These data indicate that AR is a substrate of Aurora-A and that elevated Aurora-A could contribute to androgen-independent cell growth by phosphorylation and activation of AR.
Shu
Shao-Kun
SK
From the Departments of Molecular Oncology, Tampa, Florida 33612.
Liu
Qiyuan
Q
From the Departments of Molecular Oncology, Tampa, Florida 33612.
Coppola
Domenico
D
Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
Cheng
Jin Q
JQ
From the Departments of Molecular Oncology, Tampa, Florida 33612. Electronic address: jin.cheng@moffitt.org.
D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D000728:Androgens; D011944:Receptors, Androgen; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D017430:Prostate-Specific Antigen