Role of 24‐hydroxylase in vitamin D 3 growth response of OVCAR‐3 ovarian cancer cells

Vitamin D and its analogues are potent regulators of cell growth and differentiation both in vivo and in vitro. We studied the effects of 25‐hydroxyvitamin D 3 [25(OH)D 3 ], 1,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and vitamin D analogue, EB 1089, on the growth of a human ovarian cancer cell line, OVCAR‐3. We also studied the expression of vitamin D metabolising enzymes 24‐hydroxylase (24OHase) and 1α‐hydroxylase (1αOHase). Our results showed that high concentrations (10 and 100 nM) of 1,25(OH) 2 D 3 inhibited a cell proliferation, whereas low concentration (0.1 nM) stimulated growth of the OVCAR‐3 cells. In the concentration range of 10–500 nM a prohormone, 25(OH)D 3 , stimulated growth. An amount of 1 nM EB 1089 and 100 nM 1,25(OH) 2 D 3 inhibited growth with an equal magnitude. The expression of 24OHase was strongly induced by 1,25(OH) 2 D 3 and EB 1089 in OVCAR‐3 cells, and analysis of vitamin D metabolites showed the functionality of 24OHase. An inhibition of 24OHase activity with a novel 24OHase inhibitor enhanced growth‐inhibiting effects of 1,25(OH) 2 D 3 and suppressed the growth stimulation of 100 nM 25(OH)D 3 . We also report the expression of a vitamin D activating enzyme, 1αOHase, in 7 ovarian cancer cell lines. The production of 1,25(OH) 2 D 3 in OVCAR‐3 cells was low, possibly due to an extensive activity of 24OHase or a low 1αOHase activity. These results suggest that in ovarian cancer cells vitamin D metabolizing enzymes might play a key role in modulating the growth response to vitamin D. The possible mitogenic effects of vitamin D should be considered when evaluating treatment of ovarian cancer with vitamin D. © 2003 Wiley‐Liss, Inc.