Angiogenin mediates androgen-stimulated prostate cancer growth and enables castration resistance.

Abstract

UNLABELLED:

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.

IMPLICATIONS:

The ability of angiogenin to regulate rRNA transcription and prostate cancer growth makes it a viable target for therapy.

• Authors: Shuping Li, Miaofen G Hu, Yeqing Sun, Norie Yoshioka, Soichiro Ibaragi, Jinghao Sheng, Guangjie Sun, Koji Kishimoto, Guo-Fu Hu
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 10 Pg. 1203-14 (Oct 2013) ISSN: 1557-3125 [Electronic] United States
• PMID: 23851444 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Androgens
• Angiogenesis Inducing Agents
• RNA, Ribosomal
• Receptors, Androgen
• angiogenin
• Ribonuclease, Pancreatic

Topics

• Androgens (metabolism)
• Angiogenesis Inducing Agents (metabolism)
• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Heterografts
• Humans
• Male
• Mice
• Mice, SCID
• Neoplasm Transplantation
• Promoter Regions, Genetic
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology)
• Protein Binding
• RNA, Ribosomal (genetics)
• Receptors, Androgen (genetics, metabolism)
• Ribonuclease, Pancreatic (antagonists & inhibitors, metabolism)
• Transcription, Genetic