Journal
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 127, Issue 3-5, Pages 269-275Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2011.08.010
Keywords
Vitamin D analogue; Proliferation; Invasion; PC-3; Prostate cancer
Funding
- Japan Society for the Promotion of Science [19590016, 21590022]
- Alfornso Martin Escudero Foundation (Spain)
- VR [2009-3738]
- Cancerfonden (Sweden)
- Grants-in-Aid for Scientific Research [19590016, 21590022] Funding Source: KAKEN
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The active form of vitamin D-3, 1 alpha,25-dihydroxyvitamin D-3(1 alpha,25(OH)(2)D-3), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1 alpha,25(OH)(2) D-3 therapeutic potential in treating cancers, numerous analogues have been synthesized with an attempt to increase anti-proliferative and/or decrease calcemic properties. Among these analogues, 19-nor-11 alpha,25(OH)(2)D-2 while being less calcemic has equivalent potency as 1 alpha,25(OH)(2)D-3 in several in vitro and in vivo systems. We recently showed that 19-nor-2 alpha-(3-hydroxypropyl)-1 alpha,25(OH)(2)D-3(MART-10) was at least 500-fold and 10-fold more active than 1 alpha,25(OH)(2)D-3 in inhibiting the proliferation of an immortalized normal prostate PZ-HPV-7 cells and the invasion of androgen insensitive PC-3 prostate cancer cells, respectively. In this study, we further investigated the effects of MART-10 and 1 alpha,25(OH)(2)D-3 on the dose- and time-dependent induction of CYP24A1 gene expression in PC-3 prostate cancer cells. We found that MART-10 induced CYP24A1 gene expression at a lower concentration with a longer duration compared to la.,25(OH)(2)D-3, suggesting that MART-10 is less susceptible to CYP24A1 degradation. Molecular docking model of human CYP24A1 and MART-10 indicates that its side chain is far away from the heme ion and is less likely to be hydroxylated by the enzyme. Furthermore, MART-10 was a more potent inhibitor of PC-3 cell proliferation and invasion compared to 1 alpha,25(OH)(2)D-3. In addition, MART-10 down-regulated matrix metalloproteinase-9 (MMP-9) expression which could be one mechanism whereby MART-10 influences cancer cell invasion. Finally, we observed that subcutaneous administration of MART-10 up-regulated the CYP24A1 mRNA expression in rat kidneys without affecting their plasma calcium levels. Thus, our findings demonstrate that MART-10 is biologically active in vivo and may be an effective vitamin D analogue for clinical trials to treat prostate cancer. (C) 2011 Elsevier Ltd. All rights reserved.
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