Abstract
Calcitriol (1,25(OH)2D3) is cytostatic for prostate cancer (CaP) but had limited therapeutic utility due to hypercalcemia-related toxicities, leading to the development of low-calcemic calcitriol analogs. We show that one analog, 1α-hydroxyvitamin D5 (1α(OH)D5), induced apoptosis in castration-sensitive LNCaP prostate cancer cells but, unlike calcitriol, did not increase androgen receptor (AR) transcriptional activity. LNCaP-AI, a castrate-resistant (CRCaP) LNCaP subline, was resistant to 1α (OH)D5 in the presence of androgens; however, androgen withdrawal (AWD), although ineffective by itself, sensitized LNCaP-AI cells to 1α (OH)D5. Investigation of the mechanism revealed that the vitamin D receptor (VDR), which mediates the effects of 1α (OH)D5, is downregulated in LNCaP-AI cells compared to LNCaP in the presence of androgens, whereas AWD restored VDR expression. Since LNCaP-AI cells expressed higher AR compared to LNCaP and AWD decreased AR, this indicated an inverse relationship between VDR and AR. Further, AR stimulation (by increased androgen) suppressed VDR, while AR downregulation (by ARsiRNA) stimulated VDR levels and sensitized LNCaP-AI cells to 1α (OH)D5 similar to AWD. Another cell line, pRNS-1-1, although isolated from a normal prostate, had lost AR expression in culture and adapted to androgenindependent growth. These cells expressed the VDR and were sensitive to 1α (OH)D5, but restoration of AR expression suppressed VDR levels and induced resistance to 1α (OH)D5 treatment. Taken together, these results demonstrate negative regulation of VDR by AR in CRCaP cells. This effect is likely mediated by prohibitin (PHB), which was inhibited by AR transcriptional activity and stimulated VDR in CRCaP but not castrate-sensitive cells. Therefore, in castration-sensitive cells, although the AR negatively regulates PHB, this does not affect VDR expression, whereas in CRCaP cells, negative regulation of PHB by the AR results in concomitant negative regulation of the VDR by the AR. These data demonstrate a novel mechanism by which 1α (OH)D5 prolongs the effectiveness of AWD in CaP cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 927-940 |
| Number of pages | 14 |
| Journal | Genes and Cancer |
| Volume | 1 |
| Issue number | 9 |
| DOIs | |
| State | Published - 2010 |
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Keywords
- Androgen receptor
- Calcitriol
- Prostate cancer
- Vitamin D receptor
- Vitamin D5
ASJC Scopus subject areas
- Cancer Research
- Genetics
Cite this
Androgen receptor regulation of vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-hydroxyvitamin D5 : A calcitriol analog. / Mooso, Benjamin; Madhav, Anisha; Johnson, Sherra; Roy, Mohana; Moore, Mary E.; Moy, Christabel; Loredo, Grace A.; Mehta, Rajendra G.; Vaughan, Andrew T M; Ghosh, Paramita M.
In: Genes and Cancer, Vol. 1, No. 9, 2010, p. 927-940.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Androgen receptor regulation of vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-hydroxyvitamin D5
T2 - A calcitriol analog
AU - Mooso, Benjamin
AU - Madhav, Anisha
AU - Johnson, Sherra
AU - Roy, Mohana
AU - Moore, Mary E.
AU - Moy, Christabel
AU - Loredo, Grace A.
AU - Mehta, Rajendra G.
AU - Vaughan, Andrew T M
AU - Ghosh, Paramita M
PY - 2010
Y1 - 2010
N2 - Calcitriol (1,25(OH)2D3) is cytostatic for prostate cancer (CaP) but had limited therapeutic utility due to hypercalcemia-related toxicities, leading to the development of low-calcemic calcitriol analogs. We show that one analog, 1α-hydroxyvitamin D5 (1α(OH)D5), induced apoptosis in castration-sensitive LNCaP prostate cancer cells but, unlike calcitriol, did not increase androgen receptor (AR) transcriptional activity. LNCaP-AI, a castrate-resistant (CRCaP) LNCaP subline, was resistant to 1α (OH)D5 in the presence of androgens; however, androgen withdrawal (AWD), although ineffective by itself, sensitized LNCaP-AI cells to 1α (OH)D5. Investigation of the mechanism revealed that the vitamin D receptor (VDR), which mediates the effects of 1α (OH)D5, is downregulated in LNCaP-AI cells compared to LNCaP in the presence of androgens, whereas AWD restored VDR expression. Since LNCaP-AI cells expressed higher AR compared to LNCaP and AWD decreased AR, this indicated an inverse relationship between VDR and AR. Further, AR stimulation (by increased androgen) suppressed VDR, while AR downregulation (by ARsiRNA) stimulated VDR levels and sensitized LNCaP-AI cells to 1α (OH)D5 similar to AWD. Another cell line, pRNS-1-1, although isolated from a normal prostate, had lost AR expression in culture and adapted to androgenindependent growth. These cells expressed the VDR and were sensitive to 1α (OH)D5, but restoration of AR expression suppressed VDR levels and induced resistance to 1α (OH)D5 treatment. Taken together, these results demonstrate negative regulation of VDR by AR in CRCaP cells. This effect is likely mediated by prohibitin (PHB), which was inhibited by AR transcriptional activity and stimulated VDR in CRCaP but not castrate-sensitive cells. Therefore, in castration-sensitive cells, although the AR negatively regulates PHB, this does not affect VDR expression, whereas in CRCaP cells, negative regulation of PHB by the AR results in concomitant negative regulation of the VDR by the AR. These data demonstrate a novel mechanism by which 1α (OH)D5 prolongs the effectiveness of AWD in CaP cells.
AB - Calcitriol (1,25(OH)2D3) is cytostatic for prostate cancer (CaP) but had limited therapeutic utility due to hypercalcemia-related toxicities, leading to the development of low-calcemic calcitriol analogs. We show that one analog, 1α-hydroxyvitamin D5 (1α(OH)D5), induced apoptosis in castration-sensitive LNCaP prostate cancer cells but, unlike calcitriol, did not increase androgen receptor (AR) transcriptional activity. LNCaP-AI, a castrate-resistant (CRCaP) LNCaP subline, was resistant to 1α (OH)D5 in the presence of androgens; however, androgen withdrawal (AWD), although ineffective by itself, sensitized LNCaP-AI cells to 1α (OH)D5. Investigation of the mechanism revealed that the vitamin D receptor (VDR), which mediates the effects of 1α (OH)D5, is downregulated in LNCaP-AI cells compared to LNCaP in the presence of androgens, whereas AWD restored VDR expression. Since LNCaP-AI cells expressed higher AR compared to LNCaP and AWD decreased AR, this indicated an inverse relationship between VDR and AR. Further, AR stimulation (by increased androgen) suppressed VDR, while AR downregulation (by ARsiRNA) stimulated VDR levels and sensitized LNCaP-AI cells to 1α (OH)D5 similar to AWD. Another cell line, pRNS-1-1, although isolated from a normal prostate, had lost AR expression in culture and adapted to androgenindependent growth. These cells expressed the VDR and were sensitive to 1α (OH)D5, but restoration of AR expression suppressed VDR levels and induced resistance to 1α (OH)D5 treatment. Taken together, these results demonstrate negative regulation of VDR by AR in CRCaP cells. This effect is likely mediated by prohibitin (PHB), which was inhibited by AR transcriptional activity and stimulated VDR in CRCaP but not castrate-sensitive cells. Therefore, in castration-sensitive cells, although the AR negatively regulates PHB, this does not affect VDR expression, whereas in CRCaP cells, negative regulation of PHB by the AR results in concomitant negative regulation of the VDR by the AR. These data demonstrate a novel mechanism by which 1α (OH)D5 prolongs the effectiveness of AWD in CaP cells.
KW - Androgen receptor
KW - Calcitriol
KW - Prostate cancer
KW - Vitamin D receptor
KW - Vitamin D5
UR - http://www.scopus.com/inward/record.url?scp=79952826853&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952826853&partnerID=8YFLogxK
U2 - 10.1177/1947601910385450
DO - 10.1177/1947601910385450
M3 - Article
AN - SCOPUS:79952826853
VL - 1
SP - 927
EP - 940
JO - Genes and Cancer
JF - Genes and Cancer
SN - 1947-6019
IS - 9
ER -