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 androgenstimulated 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. LXRA, LXRB, 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 receptorrich prostate cancer and modulation of LXR signaling may be a potentially useful therapy for prostate cancer. (Cancer Res 2006; 66(13): 6482-6)

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

“…AR and PSA protein expression was determined by immunoblotting using anti-AR (AN-21) and anti-PSA (DAKO, Elostrup, Denmark) antibodies as described previously [19][20][21][22][23][24].…”

“…A QuantiTect Probe PCR kit (Qiagen, Valencia, CA) and ABI Prism 7700 cycler (Applied Biosystems) were used in a dual-labeled probe protocol. Primers and probe used for androgen receptor (AR), prostate specific antigen (PSA), and sterol response element-binding protein-1c (SREBP-1c) mRNA detection were as described [24,31,32]. All transcript levels were normalized to human glyceraldehyde-3-phosphate dehydrogenase levels as described [24].…”

“…Primers and probe used for androgen receptor (AR), prostate specific antigen (PSA), and sterol response element-binding protein-1c (SREBP-1c) mRNA detection were as described [24,31,32]. All transcript levels were normalized to human glyceraldehyde-3-phosphate dehydrogenase levels as described [24]. The 5′-end and 3′-end of the all probes was labeled with the reporter-fluorescent dye (carboxyfluorescein) and quencher dye (6-carboxytetramethylrhodamine) respectively.…”

“…These androgen-independent LNCaP cells have elevated AR expression and express PSA upon androgen treatment. Androgens paradoxically inhibit the proliferation of these androgen-independent prostate cancer cells [20][21][22][23][24], which is relieved after knockdown or loss of AR expression [21,23,24]. Elevation of AR expression is often observed in advanced prostate tumors in patients [25,26].…”

“…Elevation of AR expression is often observed in advanced prostate tumors in patients [25,26]. T0901317 treatment in athymic mice delays the progression of prostate tumors towards androgen-independency [24]. Since AR and AR signaling is very important for proliferation and progression of prostate cancer cells [19][20][21][22][23][24][25][26][27] and LXR agonist T0901317 suppresses proliferation and progression of prostate cancer cells [15,24], we determined if T0901317 interacts with androgen receptor and if T0901317 affects AR signaling.…”