Androgen receptor regulation of vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-hydroxyvitamin D5

A calcitriol analog

Benjamin Mooso, Anisha Madhav, Sherra Johnson, Mohana Roy, Mary E. Moore, Christabel Moy, Grace A. Loredo, Rajendra G. Mehta, Andrew T M Vaughan, Paramita M Ghosh

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)927-940
Number of pages14
JournalGenes and Cancer
Volume1
Issue number9
DOIs
StatePublished - 2010

Fingerprint

Calcitriol Receptors
Calcitriol
Castration
Androgen Receptors
Prostatic Neoplasms
Androgens
Cytostatic Agents
1-hydroxyvitamin D5
Down-Regulation
Hypercalcemia
Prostate

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 journalArticle

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. / Androgen receptor regulation of vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-hydroxyvitamin D5 : A calcitriol analog. In: Genes and Cancer. 2010 ; Vol. 1, No. 9. pp. 927-940.
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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.",
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T1 - Androgen receptor regulation of vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-hydroxyvitamin D5

T2 - A calcitriol analog

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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

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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.

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KW - Vitamin D receptor

KW - Vitamin D5

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