Androgen Receptor Regulation of Vitamin D Receptor in Response of Castration-resistant Prostate Cancer Cells to 1α-Hydroxyvitamin D5 - a Calcitriol Analog

Overview

Journal Genes Cancer

Specialty Oncology

Date 2011 May 10

PMID 21552398

Citations 12

Authors

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

Affiliations

Soon will be listed here.

Abstract

Calcitriol (1,25(OH)(2)D3) 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, 1-α-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 androgen-independent 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 prolong the effectiveness of AWD in CaP cells.

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References

Peng X, Mehta R . Differential expression of prohibitin is correlated with dual action of Vitamin D as a proliferative and antiproliferative hormone in breast epithelial cells. J Steroid Biochem Mol Biol. 2007; 103(3-5):446-50. PMC: 1868542. DOI: 10.1016/j.jsbmb.2006.11.017. View

Choudhury A, Charo J, Parapuram S, Hunt R, Hunt D, Seliger B . Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines. Int J Cancer. 2003; 108(1):71-7. DOI: 10.1002/ijc.11497. View

Chen L, Siddiqui S, Bose S, Mooso B, Asuncion A, Bedolla R . Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells. Cancer Res. 2010; 70(14):5994-6003. PMC: 2905475. DOI: 10.1158/0008-5472.CAN-09-4440. View

Cheng H, Snoek R, Ghaidi F, Cox M, Rennie P . Short hairpin RNA knockdown of the androgen receptor attenuates ligand-independent activation and delays tumor progression. Cancer Res. 2006; 66(21):10613-20. DOI: 10.1158/0008-5472.CAN-06-0028. View

Ghosh P, Bedolla R, Mikhailova M, Kreisberg J . RhoA-dependent murine prostate cancer cell proliferation and apoptosis: role of protein kinase Czeta. Cancer Res. 2002; 62(9):2630-6. View

Nuell M, Stewart D, Walker L, FRIEDMAN V, Wood C, Owens G . Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells. Mol Cell Biol. 1991; 11(3):1372-81. PMC: 369408. DOI: 10.1128/mcb.11.3.1372-1381.1991. View

Wang Y, Kreisberg J, Bedolla R, Mikhailova M, deVere White R, Ghosh P . A 90 kDa fragment of filamin A promotes Casodex-induced growth inhibition in Casodex-resistant androgen receptor positive C4-2 prostate cancer cells. Oncogene. 2007; 26(41):6061-70. DOI: 10.1038/sj.onc.1210435. View

Brawer M . Recent Progress in the Treatment of Advanced Prostate Cancer With Intermittent Dose-Intense Calcitriol (DN-101). Rev Urol. 2007; 9(1):1-8. PMC: 1831525. View

Wang S, Fusaro G, Padmanabhan J, Chellappan S . Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression. Oncogene. 2002; 21(55):8388-96. DOI: 10.1038/sj.onc.1205944. View

10.

Petrylak D . Therapeutic options in androgen-independent prostate cancer: building on docetaxel. BJU Int. 2005; 96 Suppl 2:41-6. DOI: 10.1111/j.1464-410X.2005.05946.x. View

11.

Haag P, Bektic J, Bartsch G, Klocker H, Eder I . Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as in androgen independent prostate cancer cells. J Steroid Biochem Mol Biol. 2005; 96(3-4):251-8. DOI: 10.1016/j.jsbmb.2005.04.029. View

12.

Wang S, Nath N, Adlam M, Chellappan S . Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function. Oncogene. 1999; 18(23):3501-10. DOI: 10.1038/sj.onc.1202684. View

13.

Shi X, Xue L, Tepper C, Gandour-Edwards R, Ghosh P, Kung H . The oncogenic potential of a prostate cancer-derived androgen receptor mutant. Prostate. 2007; 67(6):591-602. DOI: 10.1002/pros.20544. View

14.

Wang Y, Mikhailova M, Bose S, Pan C, deVere White R, Ghosh P . Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene. 2008; 27(56):7106-17. PMC: 2694040. DOI: 10.1038/onc.2008.318. View

15.

Peng X, Mehta R, Wang S, Chellappan S, Mehta R . Prohibitin is a novel target gene of vitamin D involved in its antiproliferative action in breast cancer cells. Cancer Res. 2006; 66(14):7361-9. DOI: 10.1158/0008-5472.CAN-06-1004. View

16.

Peehl D, Feldman D . Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer. J Steroid Biochem Mol Biol. 2005; 92(4):307-15. DOI: 10.1016/j.jsbmb.2004.10.006. View

17.

Hawthorne M, Uselding L, Albinescu D, Moriarty R, Christov K, Mehta R . Prevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats by 1alpha-hydroxyvitamin D(5). J Natl Cancer Inst. 2000; 92(22):1836-40. DOI: 10.1093/jnci/92.22.1836. View

18.

Mehta R, Moriarty R, Mehta R, Penmasta R, Lazzaro G, Constantinou A . Prevention of preneoplastic mammary lesion development by a novel vitamin D analogue, 1alpha-hydroxyvitamin D5. J Natl Cancer Inst. 1997; 89(3):212-8. DOI: 10.1093/jnci/89.3.212. View

19.

Johnson C, Muindi J, Hershberger P, Trump D . The antitumor efficacy of calcitriol: preclinical studies. Anticancer Res. 2006; 26(4A):2543-9. View

20.

Hsieh T, Ng C, Mallouh C, Tazaki H, Wu J . Regulation of growth, PSA/PAP and androgen receptor expression by 1 alpha,25-dihydroxyvitamin D3 in the androgen-dependent LNCaP cells. Biochem Biophys Res Commun. 1996; 223(1):141-6. DOI: 10.1006/bbrc.1996.0859. View