Role of 24‐hydroxylase in vitamin D3 growth response of OVCAR‐3 ovarian cancer cells

Abstract

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 D₃ [25(OH)D₃], 1,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] 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)₂D₃ 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)D₃, stimulated growth. An amount of 1 nM EB 1089 and 100 nM 1,25(OH)₂D₃ inhibited growth with an equal magnitude. The expression of 24OHase was strongly induced by 1,25(OH)₂D₃ 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)₂D₃ and suppressed the growth stimulation of 100 nM 25(OH)D₃. We also report the expression of a vitamin D activating enzyme, 1αOHase, in 7 ovarian cancer cell lines. The production of 1,25(OH)₂D₃ 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.