Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist.

Abstract

Androgen-dependent human LNCaP 104-S tumor xenografts progressed to androgen-independent relapsed tumors (104-Rrel) in athymic mice after castration. The growth of 104-Rrel tumors was suppressed by testosterone. However, 104-Rrel tumors adapted to androgen and regrew as androgen-stimulated 104-Radp tumors. Androgen receptor expression in tumors and serum prostate-specific antigen increased during progression from 104-S to 104-Rrel but decreased during transition from 104-Rrel to 104-Radp. Expression of genes related to liver X receptor (LXR) signaling changed during progression. LXRalpha, LXRbeta, ATP-binding cassette transporter A1 (ABCA1), and sterol 27-hydroxylase decreased during progression from 104-S to 104-Rrel. These coordinated changes in LXR signaling in mice during progression are consistent with our previous findings that reduction of ABCA1 gene expression stimulates proliferation of LNCaP cells. To test if attenuation of LXR signaling may enhance prostate cancer progression from an androgen-dependent state to an androgen-independent state, castrated mice carrying 104-S tumors were given the synthetic LXR agonist T0901317 by gavage. T0901317 delayed progression from 104-S to 104-Rrel tumors. Based on our in vivo model, androgen is beneficial for the treatment of androgen-independent androgen receptor-rich prostate cancer and modulation of LXR signaling may be a potentially useful therapy for prostate cancer.

• Authors: Chih-pin Chuu, Richard A Hiipakka, John M Kokontis, Junichi Fukuchi, Rou-Yu Chen, Shutsung Liao
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 13 Pg. 6482-6 (Jul 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16818617 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• DNA-Binding Proteins
• Hydrocarbons, Fluorinated
• Liver X Receptors
• NR1H3 protein, human
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors
• Receptors, Androgen
• Receptors, Cytoplasmic and Nuclear
• Sulfonamides
• T0901317
• Testosterone
• Cholesterol
• Testosterone Propionate

Topics

• Androgens (pharmacology)
• Animals
• Cell Growth Processes
• Cholesterol (pharmacology)
• DNA-Binding Proteins (agonists)
• Disease Progression
• Humans
• Hydrocarbons, Fluorinated
• Liver X Receptors
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms, Hormone-Dependent (drug therapy, metabolism, pathology)
• Orchiectomy
• Orphan Nuclear Receptors
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, Androgen (biosynthesis, metabolism)
• Receptors, Cytoplasmic and Nuclear (agonists)
• Sulfonamides (pharmacology)
• Testosterone (blood)
• Testosterone Propionate (pharmacology)
• Xenograft Model Antitumor Assays