title: Angiogenin mediates androgen-stimulated prostate cancer growth and enables castration resistance.
abstract: The androgen receptor (AR) is a critical effector of prostate cancer development and progression. Androgen-dependent prostate cancer is reliant on the function of AR for growth and progression. Most castration-resistant prostate cancer (CRPC) remains dependent on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of prostate cancer cells. During androgen-dependent growth of prostate cells, androgen-AR signaling leads to the accumulation of rRNA. However, the mechanism by which AR regulates rRNA transcription is unknown. Here, investigation revealed that angiogenin (ANG), a member of the secreted ribonuclease superfamily, is upregulated in prostate cancer and mediates androgen-stimulated rRNA transcription in prostate cancer cells. Upon androgen stimulation, ANG undergoes nuclear translocation in androgen-dependent prostate cancer cells, where it binds to the rDNA promoter and stimulates rRNA transcription. ANG antagonists inhibit androgen-induced rRNA transcription and cell proliferation in androgen-dependent prostate cancer cells. Interestingly, ANG also mediates androgen-independent rRNA transcription through a mechanism that involves its constitutive nuclear translocation in androgen-insensitive prostate cancer cells, resulting in a constant rRNA overproduction and thereby stimulating cell proliferation. Critically, ANG overexpression in androgen-dependent prostate cancer cells enables castration-resistant growth of otherwise androgen-dependent cells. Thus, ANG-stimulated rRNA transcription is not only an essential component for androgen-dependent growth of prostate cancer but also contributes to the transition of prostate cancer from androgen-dependent to castration-resistant growth status.
  
  
  CONCLUSIONS
  The ability of angiogenin to regulate rRNA transcription and prostate cancer growth makes it a viable target for therapy.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111. ghu@tuftsmedicalcenter.org.
authors.forename: Shuping
authors.initials: S
authors.lastname: Li
authors.forename: Miaofen G
authors.initials: MG
authors.lastname: Hu
authors.forename: Yeqing
authors.initials: Y
authors.lastname: Sun
authors.forename: Norie
authors.initials: N
authors.lastname: Yoshioka
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ibaragi
authors.forename: Jinghao
authors.initials: J
authors.lastname: Sheng
authors.forename: Guangjie
authors.initials: G
authors.lastname: Sun
authors.forename: Koji
authors.initials: K
authors.lastname: Kishimoto
authors.forename: Guo-Fu
authors.initials: GF
authors.lastname: Hu
mesh_terms: D000728:Androgens / Q000378:metabolism; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D012335:RNA, Ribosomal / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000728:Androgens; D043925:Angiogenesis Inducing Agents; D012335:RNA, Ribosomal; D011944:Receptors, Androgen; C046366:angiogenin; D012259:Ribonuclease, Pancreatic